Pbl Exam 5 Case 1

Front 1

1. What four systems does the hypothalamus regulate?

Back 1

1. Homeostatic mechanisms controlling hunger, thirst, sexual desire, sleep-wake cycles
2. Endocrine control, via pituitary
3. Autonomic control
4. Limbic mechanisms

pneumonic: HEAL

Front 2

2. Where is the anterior pituitary derived from?

What is it composed of?

Back 2

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.

Front 3

3. Where is the posterior pituitary derived from?

What is it composed of?

Back 3

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.

Front 4

4. Hypothalamus - where is it located, and what are the borders?

Back 4

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.

Front 5

5. Tuber cinereum

Back 5

Means "gray protuberance", and is a bulge located between the optic chiasm and the mammillary bodies.

Front 6

6. What are the mammillary bodies?

Back 6

The mammillary bodies are paired structures that form the posterior portion of the hypothalamus.

Front 7

7. What is the infundibulum?

What is the anterior portion called?

Back 7

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.

Front 8

8. Median eminence

Back 8

The median eminence is the region where hypothalamic neurons release regulating factors that are carried by portal vessels to the anterior pituitary.

Front 9

9. Where is the pituitary gland located?

Back 9

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.

Front 10

10. Tumors in the pituitary fossa region can...

Back 10

Compress the optic chiasm causing visual problems, including bitemporal hemianopia.

Front 11

11. Where do the fibers of the fornix pass?

Back 11

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.

Front 12

12. Lateral hypothalamic area

Back 12

Consists of the lateral hypothalamic nucleus and the lateral preoptic nucleus.

Front 13

13. What is the medial forebrain bundle?

Back 13

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.

Front 14

14. Where is the periventricular nucleus located?

Back 14

Most medially, the periventricular nucleus is a thin layer of cells that lies closest to the third ventricle.

Front 15

15. Where does the preoptic area come from?

Back 15

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.

Front 16

16. Neurons in both the supraoptic and the paraventricular nuclei contain what hormones?

Back 16

Oxytocin and vasopression and then projects to the posterior pituitary.

Front 17

17. What is the importance of the suprachiasmatic nucleus?

Back 17

It is the master clock for circadian rhythms. It receives inputs from retinal ganglion cells conveying information about day-night cycles.

Front 18

18. What three things are in the middle hypothalamic region?

Back 18

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

Front 19

19. What four things are in the posterior hypothalamic region?

Back 19

1. Medial mammillary nucleus
2. Intermediate mammillary nucleus
3. Lateral mammillary nucleus
4. Posterior hypothalamic nucleus

Front 20

20. Where do the descending autonomic fibers originate from in the hypothalamus?

Back 20

Descending autonomic fiber originate mainly from the paraventricular nucleus, but also from the dorsomedial hypothalamic nucleus and from the lateral and posterior hypothalamus.

Front 21

21. Where do the descending autonomic fibers go next? Where do they synapse?

Back 21

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.

Front 22

22. Aside from the descending autonomic pathways from the hypothalamus, where are the other descending autonomic pathways?

Back 22

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.

Front 23

23. Inputs to the hypothalamus

What is one important source of input to the hypothalamus?

Back 23

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.

Front 24

24. Where does the hippocampal formation project to the hypothalamus?

Back 24

The subiculum of the hippocampal formation, a limbic structure, projects to the mammillary bodies of the hypothalamus via the FORNIX.

Front 25

25. Where do the mammillary bodies project?

Back 25

The mammillary bodies project via the mammillothalamic tract to eh anterior thalamic nucleus, which in turn projects to limb cortex in the cingulate gyrus.

Front 26

26. Amgydala pathways - two of them

Back 26

The amgydala, another important limbic structure, has reciprocal connections w/the hypothalamus via two pathways:
1. Stria terminalis
2. Ventral amygdalofugal pathway

Front 27

27. What is the importance of the limbic-hypothalamic interconnections?

Back 27

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.

Front 28

28. In addition to its roles in endocrine, autonomic, and limbic function, what else is the hypothalamus important in?

Back 28

Important in regulating a variety of appetitive, homeostatic, and other behaviors that are often essential to survival of the organism.

Front 29

29. What type of neurons in the VLPO contribute to nonREM sleep, and how?

Back 29

GABAergic neurons in the ventral lateral preoptic area contribute to nonREM sleep by inhibiting the histaminergic neurons in the tuberomammillary nucleus.

Front 30

30. Lateral hypothalamus is important in...?

Back 30

Appetite, and lesions in the lateral hypothalamus cause a decrease in body weight.

Front 31

31. Medial hypothalamus is important in...?

Back 31

Medial hypothalamus, especially the ventromedial nucleus, appears to be important in inhibiting appetite, and medial hypothalamic lesions can cause obesity.

Front 32

32. Where does leptin bind?

Back 32

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.

Front 33

33. Where does thirst come from?

Back 33

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.

Front 34

34. Role of the anterior hypothalamus?

Back 34

The anterior hypothalamus appears to detect increased body temp and activates mechanisms of heat dissipation.

Anterior hypothalamic lesions can cause hyperthermia.

Front 35

35. Role of the posterior hypothalamus?

Back 35

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.

Front 36

36. What are the six anterior pituitary hormones?

Back 36

1. Andrenocorticotropic hormone (ACTH)
2. Thyroid-stimulating hormone (TSH)
3. Growth hormone (GH)
4. Prolactin
5. Lutenizing hormone (LH)
6. Follicle-stimulating hormone (FSH)

Front 37

37. What does the intermediate lobe of the pituitary produce?

Back 37

Produces pro-opiomelanocortin (POMC) and melanocyte-stimulating hormone, and has little known clinical significance.

Front 38

38. What are the two hormones released in the posterior pituitary?

Back 38

1. Oxytocin
2. Vasopressin (ADH)

Front 39

39. What controls the release of the anterior pituitary hormones?

Back 39

Release by glandular cells in anterior pituitary is controlled by neurons in the hypothalamus through the hypophysial portal system.

Front 40

40. From where does the pituitary receive arterial blood?

Where does the first capillary plexus of the portal system occur?

Back 40

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.

Front 41

41. What nuclei project to the median eminence?

Back 41

1. Arcuate nucleus
2. Periventricular nucleus
3. Medial preoptic nucleus
4. Meidal parvocellular portions of the paraventricular nucleus

Front 42

42. What is the importance of the hypophysial portal veins?

Back 42

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.

Front 43

43. Does the posterior pituitary have a capillary plexus?

Back 43

Yes, it also has one that picks up oxytocin and vasopressin and carries these hormones into the systemic circulation.

Front 44

44. What is the importance of ACTH?

Back 44

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.

Front 45

45. What is the importance of TSH?

Back 45

TSH stimulates the thyroid to produce thyroxine (T4) and triiodothyronine (T3).

These hormones promote cellular metabolism.

Front 46

46. What is the importance of GH?

Prolactin?

Back 46

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

Front 47

47. Roles of FSH and LH?

Back 47

FSH and LH regulate ovarian hormones responsible for the menstrual cycle and oogenesis in females, and they regulate testicular hormones and spermatogenesis in males.

Front 48

48. Role of oxytocin?

Back 48

Oxytocin causes contractions of smooth muscle in the breast for milk let-down, and contractions of the uterus during labor.

Front 49

49. Role of ADH?

Back 49

ADH participates in osmotic regulation by promoting water retention by the kidneys, allowing concentration of the urine.

Front 50

50. HPA axis regulation

Back 50

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.

Front 51

51. What is a pituitary adenoma?

Back 51

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.

Front 52

52. Where do pituitary adenomas come from?

Back 52

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.

Front 53

53. What are non-functional (silent) adenomas?

Frequency of headaches in pituitary adenomas?

Back 53

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.

Front 54

54. What causes bitemporal hemianopia?

Back 54

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.

Front 55

55. What is the most commonly secreted hormone in pituitary adenomas?

Back 55

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.

Front 56

56. What are the treatment options of pituitary adenomas?

Back 56

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.

Front 57

57. What is the transsphenoidal approach used in surgery to resect pituitary adenomas?

Back 57

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.

Front 58

58. Clinical features of prolactin-secreting adenomas

Back 58

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.

Front 59

59. Dx of prolactin-secreting adenomas

Back 59

Elevated prolactin levels can have many causes, but very high levels in nonpregnant patients are virtually diagnostic of pituitary adenoma.

Front 60

60. What are the features of growth hormone secreting adenomas?

How are they diagnosed?

Back 60

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.

Front 61

61. ACTH secreting adenoma clinical features

Back 61

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.

Front 62

62. How often does Cushing's syndrome caused by primary adrenal adenomas or adenocarcinomas?

Back 62

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.

Front 63

63. What is the dexamethasone suppression test used for?

Back 63

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.

Front 64

64. When dexamethasone suppression test results are equivocal, how is petrosal sinus sampling used?

Back 64

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.

Front 65

65. TSH secreting adenomas

Back 65

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.

Front 66

66. TSH levels in hyperthyroidism caused by primary thyroid disorders vs TSH secreting pituitary adenomas

Back 66

In hyperthyroidism caused by primary thyroid disorders, TSH levels are completely suppressed.

In TSH secreting pituitary adenomas, TSH levels are elevated.

Front 67

67. What are the usual causes of hypothyroidism?

Back 67

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.

Front 68

68. What are some important symptoms resulting from hypothyroidism?

Back 68

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.

Front 69

69. LH or FSH-secreting adenomas

Back 69

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.

Front 70

70. Besides pituitary adenomas, what other lesions in this region can cause endocrine disturbances or compress the optic chiasm?

Back 70

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

Front 71

71. Are the neurons in the supraoptic and paraventricular nuclei able to release vasopressin in locations other than the posterior pituitary?

Back 71

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.

Front 72

72. What else can cause hyponatremia with elevated urine osmolarity?

Back 72

Not always caused by SIADH; can also be seen in hypovolemia or in edematous states such as heart failure or cirrhosis.

Front 73

73. Central pontine myelinolysis

Back 73

In severe cases of hyponatremia, infusions of hypertonic saline are sometimes infused too rapidly, causing central pontine myelinolysis.

Front 74

74. What is the triphasic response following surgery in the pituitary region?

Back 74

1. Diabetes insipidus shortly after surgery
2. Followed by SIADH
3. Finally, diabetes insipidus again, which may then gradually improve.

Front 75

75. What are the causes of panhypopituitarism?

Back 75

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.

Front 76

76. What is pituitary apoplexy?

Back 76

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.

Front 77

77. Anterior pituitary origin

Back 77

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.

Front 78

78. Posterior pituitary origin

Back 78

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.

Front 79

79. What are the six anterior pituitary hormones (again)?

Back 79

1. GH
2. ACTH
3. TSH
4. Prolactin
5. FSH
6. LH

Front 80

80. What are the five different types of cells that can be differentiated in the anterior pituitary?

Back 80

1. Somatotropes
2. Corticotropes
3. Thyrotropes
4. Gonadotropes
5. Lactotropes

Front 81

81. What do each of the cell types in the anterior pituitary secrete?

Back 81

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.

Front 82

82. Somatotropes stain w/what type of dye?

Back 82

Somatotropes stain strongly w/acid dyes and are therefore called acidophils.

Thus, pituitary tumors that secrete large quantities of HGH are called acidophilic tumors.

Front 83

83. Where are the posterior pituitary hormones synthesized?

Back 83

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 in the supraoptic and paraventricular nuclei of the hypothalamus.

Front 84

84.Control of the posterior pituitary

Back 84

Secretion from the posterior pituitary is controlled by nerve signals that originate int he hypothalamus and terminate in the posterior pituitary.

Front 85

85. Control of the anterior pituitary

Back 85

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.

Front 86

86. Strong olfactory stimuli

Back 86

Olfactory stimuli denoting pleasant or unpleasant smells transmit strong signal components directly and through the amygdaloid nuclei into the hypothalamus.

Front 87

87. Flow of blood in the anterior pituitary gland

Back 87

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.

Front 88

88. Where are hypothalamic releasing and inhibitory hormones secreted?

Back 88

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.

Front 89

89. How are the nerve endings in the median eminence different from most endings in the CNS?

Back 89

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.

Front 90

90. What is the function of the releasing and inhibitory hormones?

Back 90

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.

Front 91

91. What is special about growth hormone?

Back 91

Growth hormone does not function through a target gland but exerts its effects directly on all or almost all tissues of the body.

Front 92

92. Growth hormone

Back 92

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.

Front 93

93. Comparison of growth in childhood and adulthood with GH

Back 93

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.

Front 94

94. What are three specific metabolic effects of growth hormone?

Back 94

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.

Front 95

95. GH and protein deposition

Back 95

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.

Front 96

96. How does GH enhance fat utilization?

How does the rate of fat utilization compare to the rate of protein synthesis?

Back 96

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.

Front 97

97. What is the ketogenic effect of GH?

Back 97

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.

Front 98

98. What are the three effects GH has on carbohydrate metabolism?

What is responsible for these changes?

Back 98

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.

Front 99

99. What is necessary for the growth promoting action of GH?

Back 99

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.

Front 100

100. What are the three effects of growth hormone on bone?

Back 100

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

Front 101

101. What are the two principal mechanisms of bone growth in response to GH?

Back 101

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.

Front 102

102. What is the importance of somatomedins?

Back 102

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.

Front 103

103. Pygmies of Africa

Back 103

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.

Front 104

104. Duration of action of GH vs. somatomedin C

Back 104

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.

Front 105

105. What is the nature of GH secretion?

What five things stimulate GH secretion?

Back 105

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.

Front 106

106. Under acute conditions, what is a potent stimulate of GH secretion?

Back 106

Hypoglycemia is a far more potent stimulator of GH secretion than is an acute decrease in protein intake.

Front 107

107. Under chronic conditions, what is a potent stimulant of GH secretion?

Back 107

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.

Front 108

108. What part of the hypothalamus causes secretion of GHRH?

Somatostatin?

Back 108

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 controlled 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.

Front 109

109. Most of the control of growth hormone secretion is mediated through...?

Back 109

Through GHRH instead through the inhibitory hormone somatostatin.

Front 110

110. How does GHRH stimulate GH secretion?

Short term and long term effects?

Back 110

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.

Front 111

111. What happens when GH is administered directly into the blood of an animal over a period of hours?

Back 111

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.

Front 112

112. Dwarfism

Does a person w/panhypopituitary dwarfism pass through puberty?

Back 112

Most instances o dwarfism result from generalized deficiency 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.

Front 113

113. Treatment w/HGH

Back 113

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.

Front 114

114. What are the three causes of panhypopituitarism in the adult?

Back 114

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.

Front 115

115. What are three general effects that result from panhypopituitarism?

Back 115

1. Hypothyroidism
2. Depressed production of glucocorticoids by the adrenals
3. Suppressed secretion of the gonadotropic hormones so that sexual functions are lost

Front 116

116. Gigantism

Back 116

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.

Front 117

117. What are some complications of gigantism?

Back 117

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.

Front 118

118. Acromegaly

Back 118

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.

Front 119

119. What is the role of decreased GH secretion in aging?

Back 119

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.

Front 120

120. What hormones does the posterior pituitary secrete?

Back 120

ADH and oxytocin

Front 121

121. Where is ADH formed?

Oxytocin?

Back 121

ADH is formed primarily in the supraoptic nuclei

Oxytocin is formed primarily in the paraventricular nuclei

Front 122

122. Chemical structures of ADH and oxytocin

Back 122

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.

Front 123

123. What happens when ADH acts on a cell?

Back 123

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.

Front 124

124. High concentrations of ADH

Back 124

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.

Front 125

125. What are the two major hormones secreted by the thyroid?

What is the function of these hormones?

Back 125

Thyroxine (T₄)

Triiodothyronine (T₃)

Both of these hormones profoundly increase the basal metabolic rate of the body.

Front 126

126. What controls the thyroid secretion?

What else does the thyroid secrete?

Back 126

Thyroid secretion is controlled primarily by thyroid stimulating hormone (TSH) secreted by the anterior pituitary gland.

The thyroid also secretes calcitonin.

Front 127

127. How much of the thyroid hormone secretion is T₄ or T₃?

Which one is more potent?

Back 127

About 92% of the metabolically active hormones secreted by the thyroid gland is thyroxine (T₄), and 7% is triiodothyronine (T₃).

However, almost all the thyroxine is eventually converted to triiodothyronine in the tissues, so that both are functionally important.

The functions of these two hormones are the same, but they differ in rapidity and intensity of action.

T₃ is about 4x as potent as T₄, but it is present in the blood in much smaller quantities and persists for much shorter time than does T₄.

Front 128

128. Composition of the thyroid gland

Back 128

The thyroid is composed of a large number of closed follicles filled w/a secretory substance called colloid and lined w/cuboidal epithelial cells that secrete into the interior of the follicles.

The major constituent of colloid is the large glycoprotein thyroglobulin, which contains the thyroid hormones within its molecule.

The thyroid has a blood flow about 5x the weight of the gland each minute.

Front 129

129. What is required for formation of thyroxine?

Back 129

Iodine.

To form normal quantities of thyroxine, about 50 mg of ingested iodine in the form of iodides are required each year.

Front 130

130. What happens to the ingested iodides?

Back 130

Iodides ingested orally are absorbed from the GI tract into the blood in about the same manner as chlorides.

Normally, most of the iodides are rapidly excreted by the kidneys, but only after about 1/5th are selectively removed from the circulating blood by the cells of the thyroid and used for synthesis of the thyroid hormones.

Front 131

131. What is the first stage in the formation of thyroid hormones?

What is iodide trapping?

Back 131

The first stage in the formation of thyroid hormones is transport of iodides from the blood into the thyroid glandular cells and follicles.

The basal membrane of the thyroid cell has the specific ability to pump the iodide actively to the interior of the cell. This is called iodide trapping.

Front 132

132. What is the function of the iodide pump?

What is the most important factor in influences the rate of iodide trapping?

Back 132

In a normal gland, the iodide pump concentrates the iodide to about 30x its concentration in the blood.

When the thyroid becomes maximally active, this concentration ratio can rise to as high as 250x.

The rate of iodide trapping by the thyroid is influenced by several factors, the most important being the concentration of TSH.

Front 133

133. Composition of thyroid cells

Back 133

The tyroid cells are typical protein-secreting glandular cells. The ER and Golgi apparatus synthesize and secrete into the follicles a large glycoprotein molecule called thyroglobulin.

Front 134

134. What is thyroglobulin?

Back 134

Each molecule of thyroglobulin contains about 70 tyrosine AAs, and they are the major substrates that combine w/iodine to form the thyroid hormones.

Thus, the thyroid hormones form within the thyroglobulin molecule. That is, the thyroxine and triiodothyronine hormones formed from the tyrosine AAs remain part of the thyroglobulin molecule during synthesis of the thyroid hormones and even afterward as stored hormones in the follicular colloid.

Front 135

135. What is the first essential step in the formation of thyroid hormones?

What enzyme catalyzes this step?

Back 135

The first step is conversion of the iodide ions to an oxidized form of iodine, either nascent iodine (I⁰) or I₃₋, that is then capable of combining directly w/the AA tyrosine.

This oxidation of iodine is promoted by the enzyme peroxidase and its accompanying hydrogen peroxide, which provide a potent system capable of oxidizing iodides.

Front 136

136. Where is the peroxidase located?

Back 136

The peroxidase is either located in the apical membrane of the cell or attached to it, thus providing the oxidized iodine at exactly the point in the cell where the thyroglobulin molecule issues forth from the Golgi apparatus and through the cell membrane into the stored thyroid gland colloid.

When the peroxidase system is blocked or when it is hereditarily absent from the cells, the rate of formation of thyroid hormones falls to zero.

Front 137

137. What is organification?

Back 137

The binding of iodine with the thyroglobulin molecule is called organification of the thyroglobulin.

Oxidized iodine even in the molecular form will bind directly but very slowly with the AA tyrosine. In the thyroid cells, however, the oxidized iodine is associated w/an iodinase enzyme that causes the process to occur within seconds or minutes.

Therefore, almost as rapidly as the thyroglobulin molecule is released from the Golgi or as it is secreted through the apical cell membrane into the follicle, the iodine binds with about 1/6 of the tyrosine AAs within the thyroglobulin molecule.

Front 138

138. How do the thyroid hormones form from tyrosine?

Back 138

Tyrosine is first iodized to monoiodotyrosine and then to diiodotyrosine. Then, during the next few minutes, hours, and even days, more and more of the iodotyrosine residues become coupled w/one another.

The major hormonal product of the coupling reaction is the molecule thyroxine that remains part of the thyroglobulin molecule. Or, one molecule of monoiodotyrosine couples w/one molecule of diiodotyrosine to form triiodothyronine, which represents about 1/15th of the final hormones.

Front 139

139. Where is the thyroglobulin stored?

Back 139

The thyroid is unusual among endocrine glands in its ability to store large amounts of hormone.

Each thyroglobulin molecule contains up to 30 thyroxine molecules and a few triiodothyronine molecules. In this form, the thyroid hormones are stored in the follicles in an amount sufficient to supply the body w/its normal requirements of thyroid hormones for 2-3 months. Therefore, when synthesis of thyroid hormone ceases, the physiologic effects of deficiency are not observed for several months.

Front 140

140. How are the thyroid hormones released?

Back 140

Thyroglobulin itself is not released into the circulating blood in measurable amounts; instead, thyroxine and triiodothyronine must first be cleaved from the thyroglobulin molecule, and then these free hormones are released.

Front 141

141. What are the steps by which thyroid hormones are released?

Four steps:

Back 141

1. The apical surface of the thyroid cells sends out pseudopod extensions that close around small portions of the colloid to form pinocytic vesicles that enter the apex of the thyroid cell.
2. Then lysosomes in the cell cytoplasm immediately fuse with these vesicles to form digestive vesciles containing digestive enzymes from the lysosomes mixed with the colloid.
3. Multiple proteases among the enzymes digest the thyroglobulin molecules are release thyroxine and triiodothyronine in free form.
4. These then diffuse through the base of the thyroid cell into the surrounding capillaries, and into the body.

Front 142

142. What happens to 75% of the iodinated tyrosine in the thyroglobulin molecules?

Back 142

About 3/4s of the iodinated tyrosine never becomes thyroid hormones but remains monoiodotyrosine and diiodotyrosine.

During the digestion of the thyroglobulin molecule to cause release of thyroxine and triiodothyronine, these iodinated tyrosines are also freed from the thyroglobulin molecules.

However, they are not secreted into the blood. Instead, their iodine is cleaved from them by a deiodinase enzyme that makes virtually all this iodine available again for recycling withing the gland for forming additional thyroid hormones.

Front 143

143. Daily rate of secretion of thyroxine and triiodothyronine

Back 143

About 93% of the thyroid hormone released is normally thyroxine and only 7% is triiodothyronine.

However, during the ensuring few days, about one half of the thyroxine is slowly deiodinated to form additional triiodothyronine.

Therefore, the hormone finally delivered to and used by the tissues is mainly triiodothyronine, a total of about 35 micrograms per day.

Front 144

144. What immediately happens to the secreted thyroid hormones?

Back 144

On entering the blood, over 99% of the thyroxine and triiodothyronine combines immediately with several of the plasma proteins, all of which are synthesized by the liver.

They combine mainly with thyroxine binding globulin and much less so with thyroxine-binding prealbumin and albumin.

Front 145

145. Why are thyroid hormones released to the tissues slowly?

Back 145

B/c of high affinity of the plasma binding proteins for the thyroid hormones, these substances, in particular, thyroxine, are released to the tissue cells slowly. Half the thyroxine in the blood is released to the tissue cells about every 6 days, whereas half the triiodothyronine, b/c of its lower affinity, is released to the cells in about 1 day.

On entering the tissue cells, both thyroxine and triiodothyronine again bind w/intracellular proteins, the thyroxine binding more strongly than the triiodothyronine.

Front 146

146. Onset and duration of action of thyroxine

Back 146

After injection of a large amt of thyroid hormones, no effect on the metabolic rate can be discerned for 2-3 days, thereby demonstrating that there is a long latent period before thyroxine activity begins.

Once activity does begin, it increases progressively and reaches a max in 10 to 12 days. Thereafter, it decreases w/a half life of about 15 days.

Front 147

147. Onset and duration of action of triiodothyronine

Back 147

The actions of triiodothyronine occur about 4x as rapidly as those of thyroxine, with a latent period as short as 6-12 hours and maximal cellular activity occurring w/in 2-3 days.

Front 148

148. What is the general effect of thyroid hormones?

Back 148

To activate nuclear transcription of large numbers of genes.

Therefore, in virtually all cells of the body, great numbers of protein enzymes, structural proteins, transport proteins, and other substances are synthesized. The net result is generalized increase in functional activity throughout the body.

Front 149

149. Before acting on the genes to increase genetic transcription, what happens to the thyroxine?

Back 149

One iodide is removed from almost all the thyroxine, thus forming triiodothyronine.

Intracellular thyroid hormone receptors have a very high affinity of triiodothyronine. Consequently, more than 90% of the thyroid hormoen molecules that bind with the receptors is triiodothyronine.

Front 150

150. Thyroid hormones and nuclear receptors

Back 150

The thyroid hormones are either attached to the DNA genetic strands or located in proximity to them. The thyroid hormone receptor usually forms a heterodimer with retinoid X receptor (RXR) at specific thyroid hormone response elements on the DNA.

On binding w/thyroid hormone, the receptors become activated and initiate the transcription process.

Then large numbers of different types of mRNA are formed, followed within another few minutes or hours by RNA translation on the cytoplasmic ribosomes to form hundreds of new intracellular proteins.

Front 151

151. Thyroid hormones and metabolic activity

Back 151

The thyroid hormones increase the metabolic activities of almost all the tissues of the body. The basal metabolic rate can increase to 60-100% above normal when large quantities of the hormones are secreted.

Although the rate of protein synthesis is increased, at the same time the rate of protein catabolism is also increased.

The growth rate of young people is accelerated, the mental processes are excited, and the activities of most of the other endocrine glands are increased.

Front 152

152. Thyroid hormones and mitochondria

Back 152

Thyroid hormones increase the number and activity of mitochondria.

Not only do the mitochondria increase in size and number, but the total membrane surface area of the mitochondria increases almost directly in proportion to the increased metabolic rate of the whole animal.

Therefore, one of the principal functions of thyroxine might simply be to increase the number and activity of mitochondria, which in turn increases the rate of formation of ATP of energize cellular function.

Front 153

153. How to thyroid hormones affect ion transport?

Back 153

Thyroid hormones increase active transport of ions through cell membranes.

One of the enzymes that increases its activity in response to thyroid hormone in the Na-K-ATPase.

This in turn increases the rate of transport of both sodium and potassium ions through the cell membranes of some tissues.

B/c this process uses energy and increases the amt of heat produced in the body, it has been suggested that this might be one of the mechanisms by which thyroid hormones increases the body's metabolic rate.

In fact, thyroid hormone also causes the cell membranes of most cells to become leaky to sodium ions, which further activates the sodium pump and further increases heat production.

Front 154

154. What is the effect of thyroid hormone on growth?

Back 154

Thyroid hormone mainly effects growing children with growth.

In those who are hypothyroid, the rate of growth is greatly retarded. In those who are hyperthyroid, excessive skeletal growth often occurs, causing the child to become considerably taller at an earlier age. However, the bones also mature more rapidly and the epiphyses close at an early age, so that the duration of growth and the eventual height of the adult may actually be shortened.

Front 155

155. Thyroid hormones and fetal growth

Back 155

An important effect of thyroid hromoen is to promote growth and development of the brain during fetal life and for the the first few years fo postnatal life.

If the fetus does not secrete sufficient quantities of thyroid hormones, growth and maturation of the brain remains smaller than normal.

Front 156

156. Thyroid hormones and carb metabolism

Back 156

Thyroid hormone stimulates almost all aspects of carb metabolism, including rapid uptake of glucose by the cells, enhanced glycolysis, enhanced gluconeogenesis, increased rate of absorption from the GI tract, and even increased insulin secretion with its resultant secondary effects of carb metabolism.

Front 157

157. Thyroid hormones and fat metabolism

Back 157

Essentially all aspects of fat metabolism are also enhanced under the influence of thyroid hormone.

In particular, lipids are mobilized rapidly from the fat tissue, which decreases the fat stores of the body to a greater extent than almost any other tissue element. This also increases the free fatty acid concentration in the plasma and greatly accelerates the oxidation of free fatty acids by the cells.

Front 158

158. Thyroid hormones and plasma fats

Back 158

Increased thyroid homrone decreases the concentrations of cholesterol, phospholipids, and TAGs in the plasma, even though it increases the free fatty acids.

Conversely, decreased thyroid secretion greatly increases the plasma concnetrations of cholesterol, phospholipids, and TAGs and almost always causes excessive deposition of fat in the liver as well.

Front 159

159. Thyroid hormones and liver fats

Back 159

One of the mechanisms by which thyroid hormone decreases the plasma cholesterol concentration is to increase significantly the rate of cholesterol secretion in the bile and consequent loss in the feces.

A possible mechanism for the increased cholesterol secretion is that thyroid hormone induces increased numbers of LDL receptors on the liver cells, leading to rapid removal of LDLs form the plasma by the liver and subsequent secretion of cholesterol in these lipoproteins by the liver cells.

Front 160

160. Vitamin requirements and thyroid hormones

Back 160

B/c thyroid hormones increase the quantities of many bodily enzymes and because vitamins are essential parts of some of the enzymes or coenzymes, thyroid hormone causes increased need for vitamins.

Front 161

161. Thyroid hormone and basal metabolic rate, body weight

Back 161

Thyroid hormone increases metabolism in almost all cells of the body.

Greatly increased thyroid hormone almost always decreases the body weight, and greatly decreased hormone almost always increases the body weight; these effects do not always occur, b/c thyroid hormone also increases the appetite, and this may counterbalance the change in the metabolic rate.

Front 162

162. Effect of thyroid hormones on cardiac output and blood flow

Back 162

Increased metabolism in the tissues causes more rapid utilization of oxygen than normal and release of greater than normal quantities of metabolic end products from the tissues. These effects cause vasodilation in most body tissues, thus increasing blood flow.

As a consequence of increased blood flow, CO also increases.

Front 163

163. Thyroid hormones and heart rate

Back 163

The HR increases considerably more under the influence of thyroid hormone than would be expected from the increase in CO.

Therefore, thyroid hormoen seems to have a direct effect on the excitability of the heart, which in turn increases the heart rate.

This effect is of particular importance b/c the heart rate is one of the sensitive physical signs that the clinician uses in determining whether a patient has excessive or diminished thyroid production.

Front 164

164. Thyroid hormones and heart strength

Back 164

The increased enzymatic activity caused by increased thyroid hormone production apparently increases the strength of the heart. This is analogous to the increase in heart strength that occurs in mild fevers and during exercise.

However, when thyroid hormone is increased markedly, the heart muscle strength becomes depressed b/c of long-term excessive protein catabolism.

Front 165

165. Arterial pressure and thyroid hormones

Respiration?

Back 165

The mean arterial pressure usually remains about normal after administration of thyroid hormone. B/c of increased blood flow through the tissues between heartbeats, the pulse pressure is often increased, w/the systolic pressure elevated in hyperthyroidism and the diastolic pressure reduced.

The increased rate of metabolism increases the utilization of oxygen and formation of carbon dioxide. These effects activate all the mechanisms that increase the rate and depth of respiration.

Front 166

166. Thyroid hormones and GI motility

Back 166

In addition to increased appetite and food intake, thyroid homrone increases both the rates of secretion fo the digestive juices and the motility of the GI tract.

Hyperthyroidism often results in diarrhea. Lack of thyroid hormone can cause constipation.

Front 167

167. Thyroid hormones and effect of CNS

Back 167

In general, thyroid hormone increases the rapidity of cerebration but also often dissociates this; conversely, lack of thyroid hormone decreases this function.

The hyperthyroid individual is likely to have extreme nervousness and many psychoneurotic tendencies, such as anxiety complexes, extreme worry, and paranoia.

Front 168

168. Effect of thyroid hormone on muscles

Back 168

Slight increase in thyroid hormone usually makes the muscles react with vigor, but when the quantity of hormone becomes excessive, the muscles become weakened b/c of excess protein catabolism.

Conversely, lack of thyroid hormone causes the muscles to become sluggish, and they relax slowly after a contraction.

Front 169

169. Muscle tremors and thyroid hormones

Back 169

One of the most characteristic signs of hyperthyroidism is a fine muscle tremor.

It occurs at the rapid frequency of 10-15 times per second. This tremor is believed to be caused by increased reactivity of the neuronal synapses in the areas of the spinal cord that control muscle tone. The tremor is an important means for assessing the degree of thyroid hormone effect on the CNS.

Front 170

170. Thyroid levels and sleep function

Back 170

B/c of the exhausting effect of thyroid hromoen on the musculature and on teh CNS, the hyperthyroid subject often has a feeling of constant tiredness, but b/c of the excitable effects of thyroid hormone on the synapses, it is difficult to sleep.

Conversely, extreme sleepiness is characteristic of hypothyroidism, with sleep sometimes lasting 12-14 hours a day.

Front 171

171. How does thyroid hormone affect other endocrine glands?

Back 171

Increased thyroid hormone increases the rates of secretion of most other endocrine glands, but it also increases the need of the tissues for the hormones.

For instance, increased thyroxine secretion increases the rate of glucose metabolism everywhere in the body and therefore causes a corresponding need for increased insulin secretion by the pancreas.

Also, thyroid hormone increases many metabolic activities related to bone formation and, as a consequence, increases the need for PTH.

Thyroid hormone also increase the rate at which adrenal glucocorticoids are inactivated by the liver. This leads to feedback increase in adrenocorticotropic hormone production by the anterior pituitary, and therefore increased rate of glucocorticoid secretion by the adrenal glands.

Front 172

172. Thyroid and sexual functioning

Back 172

Thyroid levels to to be normal for normal sexual function.

In men, lack of them causes loss of libido; great excess of the hormone, however, sometimes causes impotence.

In women, lack of thyroid levels cause menorrhagia and polymenorrhea - that is, excessive and frequent menstrual bleeding, respectively.

A hypothyroid woman, like a man, is likely to have greatly decreased libido. Further, the hyperthyroid woman has oligomenorrhea, which means greatly reduced bleeding, is common, and occasionally amenorrhea results.

Front 173

173. What is the role of TSH?

Back 173

TSH, AKA thyrotropin, is an anterior pituitary hormone. This hormone increases the secretion of thyroxine and triiodothyronine by the thyroid gland.

Front 174

174. What are five specific effects that TSH has on the thyroid?

Back 174

1. Increased proteolysis of thyroglobulin
2. Increased activity of the iodide pump
3. Increased iodination of tyrosine to form the thyroid hormones
4. Increased size and increased secretory activity of the thyroid cells
5. Increased number of thyroid cells plus a change from cuboidal to columnar cells and much infolding of the thyroid epithelium into the follicles.

Front 175

175. What is the most important early effect after administration of TSH?

Back 175

The initiation of proteolysis of thyroglobulin, which causes release of thyroxine and triiodothyronine into the blood within 30 min. The other effects require hours or even days and weeks to develop fully.

Front 176

176. What mediates the stimulatory effect of TSH?

Back 176

Most of the effects of TSH on the thyroid cell result form activation of the cAMP system.

The first event in this activation is binding of TSH with specific TSH receptors on the basal membrane surfaces of the thyroid cell. This then activates adenylyl cyclase in the membrane, which increases the formation of cAMP inside the cell.

Finally, the cAMP acts as a second messenger to activate protein kinase which causes multiple phosphorylations throughout the cell. The result is both an immediate increase in secretion of thyroid hormones and prolonged growth of the thyroid glandular tissue itself.

Front 177

177. What regulates the anterior pituitary secretion of TSH?

Back 177

TRH, or thyrotropin releasing hormone, which is secreted by nerve endings in the median eminence of the hypothalamus. From the median eminence, the TRH is then transported to the anterior pituitary by way of the hypophysial portal system.

Front 178

178. How does TRH cause its effects?

Back 178

TRH first binds with TRH receptors in the pituitary cell membrane.

This in turn activates the phospholipase second messenger system inside the pituitary cells to produce large amounts of phospholipase C, followed by a cascade of other second messenger, including calcium ions and diacyl glycerol, which eventually leads to TSH release.

Front 179

179. What are the effect of cold and other neurogenic stimuli on TRH and TSH secretion?

Back 179

One of the best known stimuli for increasing the rate of TRH secretion by the hypothalamus, and therefore TSH secretion by the anterior pituitary gland, is exposure of an animal to cold.

Various emotional reactions can also affect the output of TRH and TSH and therefore indirectly affect the secretion of thyroid hormones.

Excitement and anxiety - conditions that greatly stimulate the sympathetic nervous system, cause and acute decrease in secretion of TSH, perhaps b/c these states increase the metabolic rate and body heat and therefore exert and inverse effect on the heat control center.

Front 180

180. What is the feedback effect of thyroid hormone?

Back 180

Increased thyroid hormone in the body fluids decreases secretion of TSH by the anterior pituitary.

Almost all this feedback depressant effect occurs even when the anterior pituitary has been separated from the hypothalamus. Therefore, it is probable that increased thyroid hormone inhibits anterior pituitary secretion of TSH mainly by a direct effect on the anterior pituitary gland itself.

Regardless of the mechanism of feedback, its effect is to maintain an almost constant concentration of free thyroid hormones in the circulating body fluids.

Front 181

181. What are the antithyroid drugs?

Back 181

These drugs suppress thyroid secretion.

The best known are thiocyanate, propylthiouracil, and high concentrations of inorganic iodides.

Front 182

182. How does thiocyanate work?

Back 182

Thiocyanate ions decrease iodide trapping.

The same iodide pump can also pump thiocyanate ions. Therefore, administration of thiocyante in high enough concentration can cause competitive inhibition of iodide transport into the cell, that is, inhibition of the iodide trapping mechanism.

The decreased availability of iodide in the glandular cells does not stop the formation of thyroglobulin; it merely prevents the thyroglobulin that is formed from becoming iodinated and therefore from forming the thyroid hormones. This deficiency leads to increased secretion of TSH, which causes overgrowth of the thyroid. Therefore, thiocyanate can cause goiter.

Front 183

183. How does propylthiouracil work?

Back 183

Propylthiouracil decreases thyroid hormone formation from iodides and tyrosine.

The mechanism of this is partly to block the peroxidase enzyme that is required for iodination of tyrosine and partly to block the coupling of two iodinated tyrosines to form thyroxine or triiodothyronine.

Propylthiouracil does not prevent formation of thyroglobulin. The absence of thyroxine and triiodothyronine can also cause goiter.

Front 184

184. How do iodides in high concentrations work?

Back 184

When iodides are present in the blood in high concentration, most activities of the thyroid are decreased, but only for a few weeks.

The effect is to reduce the rate of iodide trapping, so that the rate of iodination of tyrosine to form thyroid hormones is also decreased. Even more important, the normal endocytosis of colloid from the follicles by the thyroid glandular cells is paralyzed by the high iodide concentrations. B/c this is the first step in release of thyroid hormones from the storage colloid, there is almost immediate shutdown of thyroid hormone secretion into the blood.

High concentration of iodides can also help shrink the thyroid prior to surgery.

Front 185

185. What are the causes of hyperthyroidism?

Back 185

The changes in the thyroid in most instances are similar to those caused by excessive TSH. However, plasma TSH concentrations of lower than normal. Thus, other substance that have actions similar to those of TSH are found in the blood of almost all these patients. These substances are immunoglobulin antibodies that bind with the same membrane receptors that bind TSH.

They induce continual activation of the cAMP system of the cells, w/resultant development of hyperthyroidism.

Front 186

186. What happens to the thyroid gland in hyperthyroidism?

Back 186

In most patients w/hyperthyroidism, the thyroid is increased to 2-3x normal, w/tremendous hyperplasia and infolding of the follicular cell lining into the follicles. Also, each cell increases its rate of secretion severalfold.

Front 187

187. What are the antibodies that cause hyperthyroidism?

Back 187

These antibodies are called thyroid-stimulating immunoglobulin and are designated TSI. They have a prolonged stimulating effect on the thyroid gland, lasting for as long as 12 hours, longer than TSH.

The high level of thyroid hormone secretion caused by TSI in turn suppresses anterior pituitary formation of TSH.

The antibodies that cause hyperthyroidism almost certainly occur as the result of autoimmunity that has developed against thyroid tissue.

Front 188

188. Thyroid adenomas

Back 188

Hyperthyroidism occasionally results from a localized adenoma (a tumor) that develops in the thyroid tissue and secretes large quantities of thyroid hormone. This is not associated w/an autoimmune response.

As long as the adenoma continues to secrete large quantities of thyroid hormone, secretory function in the remainder of the thyroid gland is almost totally inhibited b/c the thyroid hormone from the adenoma depresses the production of TSH by the pituitary gland.

Front 189

189. What are the 9 symptoms of hyperthyroidism?

Back 189

1. A high state of excitability
2. Intolerance to heat
3. Increased sweating
4. Mild to extreme weight loss
5. Varying degrees of diarrhea
6. Muscle weakness
7. Nervousness or other psychic disorders
8. Extreme fatigue but inability to sleep
9. Tremor of the hands

Front 190

190. What is exopthalmos?

Back 190

Most peopel w/hyperthyroidism have some degree of protrusion of the eyeballs. It can sometimes be so severe that it stretches the optic nerve.

More often, the eyes are damaged b/c the lids can't close all the way to lubricate the eye.

The cause of the protruding eyes is edematous swelling of the retro-orbital tissues and degenerative changes in the extraocular muscles.

In most patients, immunoglobulins can be found in the blood that react w/the eye muscles. Furthermore, the concentration of these immunoglobulins is usually highest in patients who have high concentrations of TSIs.

Front 191

191. What are the diagnostic tests for hyperthyroidism?

Back 191

Most accurate test is direct measurement of the concentration fo free thyroxine in the plasma, using radioimmunoassay.

Other tests are:
1. Basal metabolic rate is usually increased to +30 to +60 in severe hyperthyroidism
2. The concentration of TSH in the plasam is measured by radioimmunoassay (look for no plasma TSH)
3. The concentration of TSI is measured by radioimmunoassay. This is usually high in thyrotoxicosis but low in thyroid adenoma.

Front 192

192. What is the treatment for a hyperplastic thyroid gland?

Back 192

Radioactive iodine. 80-90% of an injected dose of iodide is absorbed by the hyperplastic, toxic thyroid gland within 1 day after injection.

Front 193

193. Endemic colloid goiter caused by dietary iodide deficiency

Back 193

In certain areas of the world, insufficient iodine in diets leads to endemic goiters.

Lack of iodine prevents production of thyroid hormones. As a result, no hormone is available to inhibit production of TSH by the anterior pituitary; this causes the pituitary to secrete excessively large quantities of TSH. The TSH then stimulates the thyroid cells to secrete tremendous amounts of thyroglobulin colloid into the follicles, and the gland grows larger and larger.

The follicles become tremendous in size and the thyroid enlargers 10-20x normal.

Front 194

194. Idiopathic nontoxic colloid goiter

Back 194

Can occur in people who do not have iodine deficiency. The exact cause of the enlarged gland is unknown but most patients show signs of mild thyroiditis; therefore, it has been suggested that the thyroiditis causes slight hypothyroidism, which then leads to increased TSH secretion and progressive growth of the noninflamed portions of the gland.

Front 195

195. What are the four thyroid gland abnormalities in those with nontoxic colloid goiter?

Back 195

1. Deficient iodide-trapping mechanism
2. Deficient peroxidase system
3. Deficient coupling of iodinated tyrosines in the thyroglobulin molecule
4. Deficiency of the deiodinase enzyme

Front 196

196. What are the physiologic characteristics of hypothyroidism?

Back 196

Includes fatigue and extreme somnolence w/sleeping up to 12-14 hours a day, extreme muscular sluggishness, slowed heart rate, decreased CO, decreased blood volume, sometimes increased body weight, constipation, mental sluggishness, failure of many trophic function in the body evidenced by depressed growth of hair and scaliness of the skin, development of a froglike husky voice, and in severe cases, development of an edematous appearance throughout the body called myxedema.

Front 197

197. What is myxedema?

Back 197

Myxedema develops in the patient with almost total lack of thyroid hormone function.

In this condition, greatly increased quantities of hyaluronic acid and chondroitin sulfate bound w/protein form excessive tissue gel in the interstitial spaces, and this causes the total quantity of interstitial fluid to increase.

This type of edema is nonpitting type.

Front 198

198. What is cretinism?

Back 198

Cretinism is caused by extreme hypothyroidism during fetal life, infancy, or childhood. This condition is characterized especially by failure of body growth and by mental retardation. It results from congenital lack of a thyroid gland, from a failure of the thyroid to produce thyroid hormone b/c of a genetic defect of the gland, or from iodine lack in the diet.

Skeletal growth in the child w/cretinism is characteristically more inhibited than is soft tissue growth. As a result of this disproportionate rate of growth, the soft tissues are likely to enlarge excessively, giving the child w/cretinism an obese, stocky, and short appearance.

Front 199

199. What are the physiologic effects of insulin?

Back 199

Insulin stimulates the storage of glycogen in liver and muscle and the synthesis of fatty acids and TAGs and their storage in adipose tissue. In addition, insulin stimulates the synthesis in various tissues of >50 proteins, some of which contribute to the growth of the organism.

Finally, insulin has paracrine actions within the pancreatic islet cells. When insulin is release from the beta cells, it suppresses glucagon release from the alpha cells.

Front 200

200. What is glucagon and what are the related peptides?

Back 200

Glucagon is one of several contrainsular hormones. It is synthesized as part of a large precursor protein called proglucagon which is produced in the alpha cells of the pancreas and the L cells of the intestine.

It contains a number of peptides: glicentin-related peptide, glucagon, glucagon-related peptide 1 (GLP-1), and glucagon-related peptide 2 (GLP-2).

Glucagon is cleaved from proglucagon in the pancreas and the other cleavage products of proglucagon are released from the pancreas and the intestine.

Front 201

201. What are the physiologic effects of glucagon?

Back 201

Pancreatic glucagon has a half life of 3-6 minutes and is removed mainly by the liver and kidney.

Glucagon promotes glycogenolysis, gluconeogenesis, and ketogenesis by stimulating the generation of cAMP in target cells. The liver is the major target organ for glucagon.

Finally, glucagon stimulates insulin release from the beta cells of the pancreas.

Front 202

202. How do the α-cells and β-cells interact w/one another in the pancreatic islet cells?

Back 202

The pattern of blood flow in the pancreatic islet cells is believed to bathe the β-cells first and then the α-cells.

Therefore, the β-cells may influence α-cell function by an endocrine mechanism, whereas the influence of α-cell hormone on β-cell function is more likely to be paracrine.

Front 203

203. How is somatostatin formed?

Back 203

Preprosomatostatin is encoded by a gene located on the long arm of chromosome 3. Somatostatin (SS-14) is a cyclic peptide that is produced from the 14 AAs at the C-terminus of the precursor.

Somatostatin is secreted from the D-cells of the pancreatic islets, many areas of the CNS outside of the hypothalamus, and gastric and duodenal mucosal cells.

Front 204

204. Where do the different somatostatin analogues exist in the body?

Back 204

SS-14 predominates in the CNS and is the sole form secreted by the δ-cells of the pancreas.

In the gut, however, prosomatostatin (SS-28), which has 14 additional AAs, makes up 70-75% of the immunoreactivity.

The prohormone SS-28 is 7-10x more potent in inhibiting the release of GH and insulin than is SS-14.

Front 205

205. What substances stimulate somatostatin secretion?

Back 205

The metabolites that increase somatostatin release include glucose, arginine, and leucine.

The hormones that stimulate somatostatin secretion include glucagon, vasoactive intestinal polypeptide (VIP), and cholescystokinin (CCK).

Insulin, however, does not influence somatostatin secretion directly.

Front 206

206. What are the physiologic effects of somatostatin?

Back 206

Somatostatin binds to its plasma membrane receptors on target cells. These activated receptors interact w/inhibitory G-proteins of adenylate cycles, and as a result, the production of cAMP is inhibited and protein kinase A is not activated.

This inhibitory effect suppresses secretion of GH and TSH from the anterior pituitary as well as the secretion of insulin and glucagon from the pancreatic islets.

In other words "somatostatin inhibits the secretion of many other hormones"

Front 207

207. What are some other effects of somatostatin on the body?

Back 207

Somatostatin also reduces nutrient absorption from the gut by prolonging gastric emptying time, by diminishing pancreatic exocrine secretions, and by decreasing visceral blood flow.

Front 208

208. What is the therapeutic benefit of somatostatin and its synthetic analogues?

Back 208

They are used to treat a variety of secretory neoplasms such as GH secreting tumors of the pituitary.

Front 209

209. What is growth hormone?

Back 209

GH is a polypeptide that stimulates growth. Many of its effects are mediated by insulinlike growth factors (IGFs) that are produced by the cells in response to the binding of GH to its cell membrane receptors.

Front 210

210. Synthesis and secretion of GH

Back 210

The gene for GH is located on chromosome 17. It is secreted by the somatotroph cells in the lateral areas of the anterior pituitary.

GH is structurally related to human prolactin and to human chorionic somatomammotropin from the placenta.

GH is the most abundant trophic hormone in the anterior pituitary.

Front 211

211. What are the IGF-1 independent actions of GH?

(What proteins does GH produce)

Back 211

These IGF independent actions are exerted primarily in hepatocytes. GH admin is followed by an early increase in the synthesis of 8-10 proteins, among which are IGF-1, alpha2-macroglobulin, and the serine protease inhibitors Spi 2.1 and Spi 2.3.

Expression of the gene for ornithine decarboxylase is also significantly increased by GH.

Front 212

212. Muscle and adipocyte cell membranes and GH

Back 212

Muscle and adipocyte cell membranes contain GH receptors that mediate direct, rapid metabolic effects on glucose and AA transport as well as on lipolysis.

These receptors use associated cytoplasmic tryosine kinases for signal transduction.

Front 213

213. GH effects on adipose tissue

Back 213

In adipose tissue, GH has acute insulin like effects followed by increased lipolysis, inhibition of lipoprotein lipase, stimulation of hormone sensitive lipase, decreased glucose transport, and decreased lipogenesis.

Front 214

214. GH effects on muscle

Back 214

In muscle, GH causes increased AA transport, increased nitrogen retention, increased fat-free (lean) tissue, and increased energy expenditure.

Front 215

215. What is the relationship between GH receptors and IGF-1?

Back 215

GH receptors are present on a variety of tissues in which GH increases IGF-1 gene expression.

The subsequent rise in IGF-1 levels contributes to cell multiplication and differentiation by autocrine or paracrine mechanisms, which in turn lead to increased growth.

These actions are accompanied by a direct anabolic influence of GH on protein metabolism w/a diversion of AAs from oxidation to protein synthesis and a shift to a positive nitrogen balance.

Front 216

216. Stimulation of GH secretion

Back 216

The major influence is hormonal. The pulsatile pattern of GH secretion is due to two hypothalamic regulatory peptides (GHRH, and somatostatin).

Release is stimulated by GHRH, which is produced exclusively in the cells of the arcuate nucleus.

GHRH interacts w/specific receptors on the plasma membranes of the somatotrophs. The intracellular signaling mechanisms that result in GH synthesis and release appear to be multiple, as cAMP and calcium-calmodulin both stimulate GH release.

Front 217

217. What causes suppression of GH secretion?

Back 217

Somatostatin.

In addition, IGF-1, produced primarily in the liver in response to the action of GH on hepatocytes, feeds back negatively on the somatotrophs to limit GH secretion.

Front 218

218. What other things affect GH secretion?

Back 218

GH release is modulated by plasma levels of metabolic fuels, etc...

A rising level of glucose normally suppresses GH release, whereas hypoglycemia increases GH secretion.

AAs, such as arginine, stimulate GH.

Rising levels of fatty acids may blunt the GH response to arginine or a rapidly dropping blood sugar level.

However, prolonged fasting, in which fatty acids are mobilized in an effort to spare protein, is associated w/a rise in GH secretion.

Front 219

219. What are GH's effects on energy metabolism?

Back 219

GH affects the uptake and oxidation of fuels in adipose tissue, muscle, and liver and indirectly influences energy metabolism through its actions on the islet cells of the pancreas.

In sum, GH increases the availability of fatty acids, which are oxidized for energy.

This and other effects of GH spare glucose and proteins; that is, GH indirectly decreases the oxidation of glucose and AAs.

Front 220

220. What are the effects of GH on adipose tissue?

Back 220

GH increases the sensitivity of the adipocyte to the lipolytic action of insulin. This results in the release of free FAs and glycerol into the blood.

GH also decreases esterification of FAs, thereby reducing TAG synthesis.

GH may impair glucose uptake by both fat and muscle cells by a post-receptor inhibition of insulin action.

Front 221

221. What are the effects of GH on muscle?

Back 221

The lypolytic effects of GH increase free FA levels in the blood that bathes muscle.

These fatty acids are used preferentially as fuel, indirectly suppressing glucose uptake by muscle cells, and thus the rate of glycolysis is reduced.

GH increases the transport of AAs into muscle cells, providing substrate for protein synthesis. It also increases the synthesis of DNA and RNA.

Front 222

222. What are the effects of GH on the liver?

Back 222

When plasma insulin levels are low, GH enhances fatty acid oxidation to acetyl CoA, which enhances ketogenesis, and thus gluconeogenesis is enhanced. Hepatic glycogen synthesis is also stimulated.

A major effect of GH on liver to stimulate production and release of IGFs.

Front 223

223. What are the IGFs and what do they do?

Back 223

AKA somatomedins. The two somatomedins in humans are similar to insulin, hence IGF.

IFG-1 is a single chain basic peptide, whereas IGF-2 is slightly acidic.

In most instances, IGF-1 causes increased thymidine uptake and initiates cell propagation, but to a lesser extent than insulin and at a smaller concentration.

Thus, the IGFs are more potent than insulin in their growth promoting actions.

Front 224

224. How do IGFs work?

Back 224

They exert their effects through either an endocrine or a paracrine/autocrine mechanism.

IGF-1 appears to stimulate cell propagation and growth by binding to specific IGF-1 receptors on the plasma membrane of target cells, rather than binding to GH receptors.

Front 225

225. What is the composition of the intracellular membrane receptor for IGFs?

Back 225

The intracellular portion of the plasma membrane receptor for IGF-1 (but not IGF-2) has intrinsic tyrosine kinase activity, which suggests that tyrosine phsophorlation initiates cell replication and growth.

Subsequently, a chain of kinases is activated, which include a number of proto-oncogene products.

Front 226

226. Where are IGFs located in the body?

What regulates their synthesis?

Back 226

Most cells of the body have mRNA for IGF, but the liver has the greatest concentration of these messengers, followed by the kidney and heart.

The synthesis of IGF-1 is regulated by GH, whereas hepatic production of IGF-2 is independent of GH levels in the blood.

Front 227

227. What are the catecholamines?

Back 227

They are bioamines and are secretory products of the sympathoadrenal system. They are required for the body to adapt to great variety of acute and chronic stresses.

Epinephrine is synthesized primarily in the cells of the adrenal medulla, whereas norepinephrine is synthesized there as well as in various areas of the CNS.

They all come from the precursor tyrosine.

Front 228

228. What stimulates the secretion of catecholamines?

Back 228

Secretion of epinephrine and norepinephrine from the adrenal medulla is stimulated by stresses such as pain, hemorrhage, exercise, hypoglycemia, and hypoxia.

Release is mediated by stress induced transmission of nerve impulses emanating from adrenergic nuclei in the hypothalamus.

These impulses cause depolarization fo the plasma membranes which allow the rapid entry of calcium into the cytosol which stimulates the release of epinephrine and norepinephrine form the chromaffin granules into the extracellular space by exocytosis.

Front 229

229. What are the physiologic effects of epinephrine and norepinephrine?

Back 229

They act on two major types of receptors, α-adrenergic and the β-adrenergic receptors.

These catecholamines are counterregulatory hormones that have metabolic effects directed toward mobilization of fuels from their storage sites for oxidation by cells to meet increased energy needs. They simultaneously suppress insulin secretion.

They have a relatively low affinity for both α- and β-receptors. After binding, they dissociate from the receptor, causing the duration of biologic response to be brief.

Front 230

230. Norepinephrine

Back 230

Works as a neurotransmitter that affects the sympathetic nervous system in the heart, lungs, blood vessels, bladder, gut, and other organs.

These effects of catecholamines on the heart and blood vessels increase cardiac output and systemic blood pressure, hemodynamic changes that facilitate the delivery of blood borne fuels to metabolically active tissues.

Front 231

231. Epinephrine

Back 231

Epinephrine has a short half life in the blood, and to be effective pharmacologically, it must be administered parenterally. It may be used clinically to support the beating of the heart, to dilate inflamed bronchial muscles, and even to decrease bleeding from organs during surgery.

Epinephrine also inhibits insulin release while stimulating glucagon release from the pancreas.

Front 232

232. What are the glucocorticoids?

Back 232

Cortisol is the major glucocorticoid in humans. They raise blood glucose levels and protect the body from insulin induced hypoglycemia.

Front 233

233. How are glucocorticoids secreted?

Back 233

Via a cascade of neural and endocrine signals linked in tandem w/the HPA axis.

Stresses elicit the production of monoamines (ACh and serotonin) in the cell bodies of neurons of the midbrain. These neurotransmitters then induce the production of CRH by neurons originating in the paraventricular nucleus, which release CRH into the hypophysial portal system.

CRH is then delivered to the receptors on the anterior pituitary which cause it to release ACTH.

ACTH is then released and goes to the adrenal cortex, which causes cortisol synthesis and release.

Front 234

234. How does ACTH directly influence cortisol synthesis?

Back 234

The major trophic effect of ACTH on cortisol synthesis is at the level of the conversion of cholesterol to pregnenolone, from which the adrenal steroid hormones are derived.

Front 235

235. What are the effects of glucocorticoids?

Back 235

They stimulate lipolysis in adipose tissue and the release of AAs from muscle protein.

In the liver, glucocorticoids stimulate gluconeogenesis and the synthesis of glycogen.

When GCs are elevated, glucose uptake by the cells of many tissues in inhibited, lypolysis occurs in fat, and proteolysis occurs in skin, lymphoid cells, and muscle.

The fatty acids that are released are oxidized by the liver for energy.

Front 236

236. What is the mechanism by which GCs exert their effects on the body?

Back 236

Involves binding of the steroid to intracellular receptors, interaction of the steroid-receptor complex w/GC response elements on DNA, transcription of genes, and synthesis of specific proteins.

Front 237

237. What are the effects of thyroid hormone on the liver?

Back 237

Thyroid hormone increases glycolysis and cholesterol synthesis and increases the conversion of cholesterol to bile salts.

It also increases hepatic TAG synthesis. The concurrent increase in the flow of glycerol to the liver (as a result of increased lipolysis) further enhances hepatic gluconeogenesis.

Front 238

238. What are the effects of thyroid hormone on adipocytes?

What is the major determinant of the rate of lipogenesis?

Back 238

Thyroid hormones have an amplifying or facilitatory effect on the lipolytic action of epinephrine on fat cells. Yet thyroid hormone has a bipolar effect on lipid storage, b/c it increases the availability of glucose to the fat cell, which serves as a precursor for fatty acid and glycerol 3-phosphate synthesis.

The major determinant of the rate of lipogenesis, however, is not thyroid hormone, but rather the amt of glucose and insulin available to the adipocyte for TAG synthesis.

Front 239

239. Effect of thyroid hormone on muscle

Back 239

It increases glucose uptake by muscle cells. It also stimulates protein synthesis and muscle growth through its stimulatory actions on gene expression.

It also sensitizes the muscle cell to the glycogenolytic actions of epinephrine. Glycolysis in muscle is increased as a result.

Front 240

240. What are the effects of thyroid hormone on the pancreas?

Back 240

Thyroid hormone increases the sensitivity of the β-cells of the pancreas to those stimuli that normally promote insulin release and is required for optimal insulin secretion.

Front 241

241. Norepinephrine and brown fat

Back 241

Thyroid hormoen stimulates the sympathetic nervous ststem by increasing the release of norepinephrine.

Norepinephrine stimulates the uncoupling protein thermogenin in brown adipose tissue which increases heat production.

It also increases the permeability of brown fat and skeletal muscle to sodium, which increases the basal metabolic rate due to increase activity of Na-K-ATPase.

Front 242

242. Gastrin, Motilin, Pancreatic polypeptide, Peptide YY, and Secretin

Back 242

Gastrin induces gastric acid secretion , which ultimately affects nutrient absorption and metabolism.

Motilin stimulates gastric and pancreatic enzyme secretion.

Pancreatic polypeptide from the pancreatic islets reduces gastric emptying and slows upper intestinal motility.

Peptide YY from the alpha cells in the islets inhibits gastric acid secretion.

Secretin produced by the endocrine S cells in the proximal small bowel regulates pancreatic enzyme secretion and inhibits gastrin release and secretion of gastric acid.

Front 243

243. What are GLP-1 and GIP?

Back 243

They are gastrointestinal peptides; glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptic (GIP).

They do not act as direct insulin secretagogues when blood glucose levels are normal but do so after a meal large enough to cause an increase in the blood glucose concentration. THey may be responsible for the modest postprandial increase in serum glucose.

Likewise, this effect (certain factors potentiating insulin release), known as the incretin effect could account for the greater β-cell response seen after an oral glucose load compared to that seen after the administration of glucose intravenously.

Front 244

244. What are the actions of GLP-1 and GIP?

Back 244

Both GLP-1 and GIP enhance the synthesis and release of insulin as well as exerting a positive influence on the survival of pancreatic islet cells.

In addition, GLP-1 contributes to the regulation of glucose homeostasis by inhibiting the secretion of glucagon from the alpha cells of the pancreas as well as by slowing the rate of gastric emptying.

GIP, but not GLP-1, interacts w/GIP receptors on adipocytes, an interaction that is coupled to energy storage.

Front 245

245. What is the clinical significance of the incretins?

Back 245

The recent introduction of incretin-related agents indicated for the treatment of type 2 DM has shown promising results.

Exanatide is an agonist of the GLP-1 receptor and must be administered subcutaneously.

Sitagliptin is an orally administered inhibitor of DPP4. Through its action, sitagliptin slows the rate of catalytic cleavage of GIP and GLP-1 by DPP4 and therefore prolongs their half lives in the blood.

Front 246

246. How do neural factors control secretion of insulin and counterregulatory hormone?

Back 246

Although stimulation of both the sympathetic and the parasympathetic systems increases glucagon secretion, insulin secretion is increased by vagus nerve fibers and suppressed by sympathetic fibers via the alpha-adrenoreceptors.

Evidence also suggests that the sympathetic nervous system regulates pancreatic β-cell function indirectly, though stimulation or suppression of the secretion of somatostatin, β₂-adrenergic receptor number, and the neuropeptides, neuropeptide Y and galanin.

Front 247

247. What are the functions of the endocannabinoid system? (CB1 only)

Back 247

The CB1 receptor is expressed in many tissues, including adipose tissue, muscle, liver, the GI tract, the pancreas, and the CNS. The functions of the ECS in the brain influence energy metabolism.

Front 248

248. What are the two mechanisms by which the ECS influences energy metabolism?

Back 248

1. The ability of the cannabinoids to modulate signaling from hypthalamic nuclei to most of the trophic hormone-producing cells of the anterior pituitary gland. CB1 receptors have also be found in the thyroid and adrenals.

2. CB1 receptor activation induces hyperphagia, particularly for highly palatable foods even in satiated animals.

Front 249

249. What is tolbutamide?

Back 249

Tolbutamide is a sulfonylurea drug that increases insulin secretion, and also increases the secretion of pancreatic somatostatin.

Front 250

250. What is the major limitation in the clinical use of native somatostatin?

Back 250

It has short half life of less than 2 minutes in the circulation.

Analogs of native somatostatin, however, are resistant to degradation, and therefore, have a longer half life, such as octreotide.

Front 251

251. Oral glucose load tests and acromegaly

Back 251

Patients are given 100 g glucose syrup. This does would suppress serum GH levels to <2 ng/mL in normal subjects, but not in patients with acromegaly who have an autonomously secreting pituitary tumor making GH.

Front 252

252. GH excess and peripheral effects

Back 252

GH stimulates IGF-1 gene expression not only in the liver but in a number of extrahepatic tissues as well.

In acromegalics, rising levels of IGF-1 cause a gradual generalized increase in skeletal, muscular, and visceral growth.

As a consequence, a diffuse increase occurs in the bulk of all tissues, especially in the peripheral tissues.

Front 253

253. What is an important consequence of excess GH?

Back 253

DM

Front 254

254. High levels of IGF-1 have been linked to...?

Back 254

The development of breast, prostate, colon, and lung CA.

Additionally, experimental modulation of IGF-1 receptor activity can alter the growth of different types of tumor cells.

Front 255

255. What is pheochromocytoma?

Back 255

A patient who has consistently elevated levels in the blood or urine should be considered to have a pheochromocytoma, particularly if the patient has signs and symptoms of catecholamine excess, such as excessive sweating, palpitations, tremulousness, and hypertension.

Front 256

256. Why would pheochromocytoma lead to impaired glucose tolerance?

Back 256

The catecholamines are counterregulatory hormones tha tmobilize fuels from their storage sites for oxidation in target cells to meet the increased energy requirements that occur during acute or chronic stress.

These actions provide the liver with increased levels of substrate needed for gluconeogenesis. This increases the glucose levels in the blood.

In addition, the catecholamines suppress insulin secretion to ensure that fuels will continues to flow in the direction of utilization rather than storage under these circumstances.

Front 257

257. If a patient has Cushings disease from a neoplasm of the adrenal cortex, what would the levels of blood ACTH and cortisol be?

Back 257

If the problem is due to a primary hypersecretion of cortisol by a neoplasm the blood cortisol levels would be elevated. The increased cortisol levels would have decreased the ACTH levels in the blood.

However, if both cortisol and ACTH levels are elevated, then the tumor is most likely in the pituitary gland or ectopic ACTH tumors.

Front 258

258. What is Refetoff disorder?

Back 258

In Refetoff disorder, a mutation in the portion of the gene that encodes the ligand binding domain of the beta-subunit of the thyroid hormone receptor protein causes a relative resistance to the suppressive action of thyroid hormone on the secretion of TSH by the thyrotrophs of the anterior pituitary gland.

Therefore, the gland releases more TSH than normal into the blood. The elevated level of TSH causes goiter as well as an increase in the secretion of thyroid hormones into the blood.

If the compensatory increase in the secretion of thyroid hormones is inadequate, the patient may develop the signs and symptoms of hypothyroidism.

Front 259

259. What is metathyroid diabetes mellitus?

Back 259

In hypothyroid patients, insulin release may be suboptimal, although glucose intolerance on this basis alone is uncommon.

In hyperthyroidism, the degradation and the clearance of insulin are increased. These effects may lead to varying degrees of glucose intolerance, called metathyroid diabetes mellitus.

Front 260

260. What are the names of the growth hormone and insulin-like growth factor replacements?

Back 260

1. Somatotropin
2. Somatrem (GH)
3. Sermorelin (GHRH)
4. Hexarelin
5. Ghrelin
6. Mecasermin

Front 261

261. Somatropin and somatrem

Back 261

MOA: Replacement recombinant HGH; somatrem is chemically identical apart from an additional N-terminus methionine.

PURPOSE: Growth failure in children w/GH deficiency, Turners, Prader-Willi, and chronic kidney disease; idiopathic short stature; replacement of endogenous GH in adults w/GH deficiency; AIDS wasting or cachexia.

ADVERSE: Leukemia, increased ICP, pancreatitis, rapid growth of melanocytic lesions; hyperglycemia, peripheral edema, injection site reaction, arthralgia, headache

CONTRA: Patients w/closed epiphyses, active underlying intracranial lesions, active malignancy, proliferative diabetic retinopathy

NOTES: Caution in diabetes and in children whose GH deficiencies results from an intracranial lesion; available as depot injection; glucocorticoids inhibit growth promoting effect of somatropin.

Front 262

262. Sermorelin

Back 262

MOA: Synthetic GHRH

PURPOSE: Diagnostic eval of decreased plasma GH; treatment of GH deficiency; GH therapy in children w/tertiary (hypothalamic) deficiency

ADVERSE: Transient flushing, chest tightness, injection site reaction, antibody development

CONTRA: Do not use w/another drug that affects pituitary gland

NOTES: Caution in children whose GH deficiency results from an intracranial lesion.

Front 263

263. Hexarelin and Ghrelin

Back 263

MOA: Promotes somatotroph secretion of GH by stimulating the GH secretagogue receptor

PURPOSE: Investigational

ADVERSE: Flushing, weight gain, drowsiness

NOTES: Experimental agents that bind to GH secretagogue receptors; Hexarelin formulations available for intranasal use

Front 264

264. Mecasermin

Back 264

MOA: Recombinant IGF-1

PURPOSE: Laron dwarfism, GH deficiency w/neutralizing antibodies

ADVERSE: Hypoglycemia, slipped upper femoral epiphysis, raised ICP, seizure, tonsillar hypertrophy, injection site reaction

CONTRA: Growth promotion in patients w/closed epiphyses, suspected or active neoplasm

NOTES: Available as a twice-daily and one-daily injection

Front 265

265. What are the three agents that decrease GH secretion or actions?

Back 265

1. Octreotide
2. Somatostatin
3. Pegvisomant

Front 266

266. Octreotide

Back 266

MOA: Inhibits GHRH release by acting as an analogue of somatostatin

PURPOSE: Acromegaly, flushing and diarrhea from carcinoid tumors, carcinoid crisis, diarrhea from vasoactive intestinal peptide-secreting tumors

ADVERSE: Arrhythmias, bradycardia, hypoglycemia, gallstone formation, abdominal pain, consitpation, diarrhea, nausea, vomiting

CONTRA: Hypersensitivity to octreotide

NOTES: Also used to control GI bleeding and to reduce secretory diarrhea; octreotide also available in depot formulation; decreases cyclosporine levels, Lanreotide is similar agent in UK

Front 267

267. Somatostatin

Back 267

MOA: Inhibits GHRH release

PURPOSE: VIPomas, carcinoid tumors, enterocutaneous and pancreatic fistulas, short-bowel syndrome

ADVERSE: Arrhythmias, erythroderma, life-threatening water retention, glucose intolerance

CONTRA: Hypersensitivity to somatostatin

NOTES: Upon discontinuation, may experience rebound hormonal hypersecretion; reduces analgesic effects of morphine

Front 268

268. Pegvisomant

Back 268

MOA: Competitive antagonist of GH receptors; decreases serum IGF-1 levels.

PURPOSE: Acromegaly

ADVERSE: Increased pituitary adenoma size, elevated LFTS, hypertension, peripheral edema, paresthesias, dizziness

CONTRA: Hypersensitivity to pegvisomant

NOTES: Patients should have yearly MRI to exclude enlarging adenoma

Front 269

269. What are the four agents that decrease prolactin levels?

Back 269

1. Bromocriptine
2. Pergolide
3. Quinoglide
4. Cabergoline

Front 270

270. Bromocriptine (MOA, PURPOSE, and ADVERSE)

Back 270

MOA: A synthetic dopamine receptor agonist that inhibits lactotroph cells growth (decreases prolactin levels)

PURPOSE: Amenorrhea and galactorrhea from hyperprolactinemia, acromegaly, Parkinson's disease, premenstrual syndrome, Cushing syndrome, hepatic encepaholopathy, neuroleptic malignant syndrome related to neuroleptic drug therapy

ADVERSE: Cerebral vascular accident, seizure, acute myocardial infarction, dizziness, hypotension, abdominal cramps, nausea

Front 271

271. Bromocripitine (CONTRA and NOTES)

Back 271

Bromocriptine

CONTRA: Hypersensitivity to ergot derivatives, uncontrolled hypertension, toxemia of pregnancy

NOTES:
1. Ergot alkaloid; dose 2x/day
2. Intravaginal administration may reduce GI side effects
3. Alcohol intolerance may occur
4. First dose phenomenon occurs in 1% of patients and may result in syncope
5. Coadministration w/amitriptyline, butryophenones, imipramine, methyldopa, phenothiazines, or reserpine causes increased prolactin levels
6. Coadministration w/antihypertensives potentiates hypotension

Front 272

272. Pergolide, quinoglide, cabergoline

Back 272

MOA: Also dopamine receptor agonists that decrease prolactin levels

PURPOSE: Parkinson's disease (pergolide and cabergoline), hyperprolactinemia

ADVERSE: Arrhythmias, MI, heart failure, pulmonary fibrosis and pleural effusion (cabergoline), nausea, dizziness, dyskinesia, dystonia, hallucinations, somnolence, orthostatic hypotension, rhinitis

CONTRA: Hypersensitivity to ergot derivatives and uncontrolled hypertension

NOTES:
1. Use cautiously in patients prone to arrhythmias and underlying psychiatric disorders
2. Use cautiously in patients w/history of pleuritis, pleural effusion, pleural fibrosis, pericarditis, cardiac valvulopathy, or retroperitoneal fibrosis
3. CNS depressants have additive effects
4. Quinoglide and cabergoline are nonergots
5. *Cabergoline produces less nausea than bromocriptine or pergolide

Front 273

273. What are the agents that test thyroid function?

Back 273

1. Protirelin (TRH)
2. Thyrotropin (TSH)

Front 274

274. Protirelin

Back 274

MOA: TRH stimulates TSH release from pituitary

PURPOSE: Diagnosis of thyroid function

ADVERSE: Seizure, amaurosis fugax (transient monocular visual loss) in patients w/pituitary tumors, anxiety, diaphoresis, hyper- and hypotension

CONTRA: none

NOTES: Transient changes in BP can occur immediately following administration; Cyproheptadine and thioridazine decrease protirelin-mediated TSH response

Front 275

275. Thyrotropin

Back 275

MOA: TSH stimulates thyroid gland

PURPOSE: Diagnosis of malignant tumor of thyroid gland

ADVERSE: Anaphylactoid reaction w/repeated administration; nausea, vomiting, asthenia, headache

CONTRA: Adrenal insufficiency, coronary thrombosis

Front 276

276. What are the agents that test adrenal function?

Back 276

Corticotripin (ACTH) and Cosyntropin (ACTH 1-24)

Front 277

277. Corticotropin (ACTH) and Cosyntropin (ACTH 1-24)

MOA, PURPOSE, and ADVERSE

Back 277

MOA: Stimulates adrenal cortisol and androgen production

PURPOSE: Dx of adrenocortical function, exacerbation of MS, severe allergic reactions, collagen disorder, dermatologic disorders, inflammation, infantile spasms

ADVERSE: Increased ICP w/papilledema, pseudotumor cerebri, seizures, heart failure, necrotizing vasculitis, shock, pancreatitis, peptic ulceration w/perforation, hypokalemic alkalosis, induction of latent DM, bronchospasm; dizziness

Front 278

278. Corticotropin (ACTH) and Cosyntropin (ACTH 1-24)

CONTRA and NOTES

Back 278

Corticotropin (ACTH) and Cosyntropin (ACTH 1-24)

CONTRA: Patients w/peptic ulcer, scleroderma, osteoporosis, systemic fungal infections, ocular herpes simplex, heart failure, hypertension, sensitivity to pork, recent surgery, adrenocortical hyperfunction or primary insufficiency, or Cushing's syndrome

NOTES:
1. Cosyntropin (contains first 24 AA residues of ACTH) is less antigenic and less likely to cause allergic reactions than corticotropin (contains all 39 AA residues of ACTH)
2. Patients w/suspected sensitivity to porcine proteins should undergo skin testing
3. Observe neonates of corticotropin treated women for signs of hypoadrenalism
4. Counteract edema by low-sodium, high potassium intake
5. Coadministration w/NSAIDs increases risk of GI bleeding
6. Corticotropin increases plasma levels of digoxin

Front 279

279. What are the agents that alter gonadatropin expression?

Back 279

1. Gonadorelin
2. Goserelin
3. Histrelin
4. Leuprolide
5. Nafarelin
6. Follitropin (rFSH)
7. Urofollitropin (FSH)
8. Ganirelix
9. Cetrorelix
10. Abarelix

Front 280

280. Gonadorelin

Back 280

MOA: GnRH receptor agonists; Continuous: inhibit LH and FSH release; Pulsatile: stimulate LH and FSH release

PURPOSE: Dx of hypogonadism, stimulate ovulation

ADVERSE: Anaphylaxis w/multiple administrations, lightheadedness, flushing, headache

CONTRA: None

NOTES: Normal response to gonadorelin testing indicates the presence of functional pituitary gonadotropes; pulsatile form for stimulation of ovulation

Front 281

281. Gosereline, histrelin, leuprolide, nafarelin

Back 281

MOA: GnRH receptor agonists; Continuous: inhibit LH and FSH release; Pulsatile: stimulate LH and FSH release

PURPOSE: all four agents are used in breast and prostate CA's, endometriosis, precocious puberty, acute intermittent porphyia

ADVERSE: Deep venous thrombosis (goserelin, leuprolide), pituitary apoplexy (leuprolide); hot flashes, gynecomastia, osteoporosis, transient pain, sexual dysfunction

CONTRA: hypersensitivity to LHRH or LHRH analogues, pregnancy

NOTES: Depot formulations that result in gonadotropin suppression and consequent decreased gonadal steroids;
*Can initially increase testosterone and estrogen levels

Front 282

282. Follitropin (rFSH) and Urofollitropin (FSH)

Back 282

MOA: GnRH receptor agonists; stimulate ovulation

PURPOSE: Ovulation induction, male hypogonadotropic hypogonadism

ADVERSE: embolism and thrombosis, ARDS, ovarian hyperstimulation syndrome; ovarian cysts and hypertrophy, upper respiratory infection

CONTRA: Any endocrine disorder other than anovulation: abnormal uterine bleeding, primary gonadal failure, pituitary tumor, ovarian cyst or enlargement of unknown origin, pregnancy, sex-hormone dependent tumors, thyroid or adrenal dysfunction

NOTES: May result in multiple fetuses.

Front 283

283. Ganirelix, cetrorelix, and abarelix

Back 283

MOA: GnRH receptor antagonists

PURPOSE: Ovulation induction (ganirelix and cetrorelix); prostate CA (abarelix)

ADVERSE: QT interval prolongation (abarelix), ectopic pregnancy, thrombotic disorder, spontaneous abortion (ganirelix), anaphylaxis (cetrorelix), ovarian hyperstimulation syndrome

CONTRA: Pregnancy, lactation, ovarian cysts, or enlargement not due to polycystic ovarian syndrome, primary ovarian failure, sex-hormone dependent tumors, thyroid or adrenal dysfunction, vaginal bleeding of unknown etiology

Front 284

284. What are the names of the vasopressin antagonists?

Back 284

Conivaptan and tolvaptan

Front 285

285. Conivaptan and tolvaptan

Back 285

MOA: Mixed V1/V2 receptor antagonists

PURPOSE: Euvolemic hyponatremia and heart failure (investigational)

ADVERSE: hypertension, orthostatic hypotension, injection site reaction, hypokalemia, increased thirst, polyuria

CONTRA: Concurrent use of potent P450 3A4 inhibitors, hypovolemic hyponatremia

NOTES: B/c conivaptan is a P450 3A4 substrate, it is contraindicated to use this drug concurrently w/P450 3A4 inhibitors such as ketokconazole, itraconazole, ritonavir, clarithromycin, and indinavir; tolvaptan is an investigational agent specific for V2 receptors

Front 286

286. What are the manifestations of anterior pituitary disease?

Posterior pituitary disease?

Back 286

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.

Front 287

287. What is the most common cause of hyperpituitarism?

Back 287

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.

Front 288

288. Functional vs. silent adenomas

Back 288

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.

Front 289

289. How are pituitary adenomas classified?

Back 289

On the basis of hormone(s) produced by the neoplastic cells detected by immunohistochemical stains performed on tissue section.

Front 290

290. Microadenomas vs. macroadenomas

Back 290

Pituitary adenomas are designated microadenomas if they are less than 1 cm in diameter and macroadenomas if they exceed 1 cm in diameter.

Front 291

291. Monoclonal origin of pituitary adenomas

Back 291

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.

Front 292

292. What are the best characterized molecular abnormalities in pituitary adenomas?

Back 292

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.

Front 293

293. What encodes the α-subunit on the Gs-protein?

Back 293

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.

Front 294

294. GNAS1 mutations

Back 294

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.

Front 295

295. GNAS1 mutations are associated with what type of adenomas?

Back 295

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.

Front 296

296. MEN-1

Back 296

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.

Front 297

297. What molecular abnormalities are present in aggressive or advanced pituitary adenomas?

Back 297

Activating mutations of the RAS oncogene and overexpression of the c-MYC oncogene, suggesting that these genetic events are linked to disease progression.

Front 298

298. What is the morphology of pituitary adenomas?

Back 298

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.

Front 299

299. Location of large pituitary adenomas

Back 299

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.

Front 300

300. What distinguishes pituitary adenomas from non-neoplastic anterior pituitary parenchyma?

Back 300

Cellular monomorphism and the absence of a significant reticular network distinguish pituitary adenomas from non-neoplastic anterior pituitary parenchyma.

Front 301

301. What are the most frequent type of hyperfunctioning pituitary adenomas?

Back 301

Prolactinomas (lactotroph adenomas) are the most frequent, accounting for about 30% of all clinically recognized pituitary adenomas.

Front 302

302. Prolactinomas

Back 302

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).

Front 303

303. Prolactinomas and Prl (prolactin)

Back 303

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.

Front 304

304. Increased levels of prolactin cause...?

Back 304

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.

Front 305

305. What other things can cause hyperprolactinemia?

Back 305

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.

Front 306

306. GH (somatotroph cell) adenomas

Back 306

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.

Front 307

307. Densely granulated vs sparsely granulated GH adenomas

Back 307

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.

Front 308

308. What are bihormonal mammosomatotroph adenomas?

Back 308

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.

Front 309

309. What causes the clinical manifestations in GH adenomas?

Back 309

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.

Front 310

310. What is necessary for a Dx of pituitary GH excess?

Back 310

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.

Front 311

311. Corticotroph adenomas

Back 311

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.

Front 312

312. What does excess production of ACTH by the corticotroph adenoma lead to?

Back 312

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.

Front 313

313. What is Nelson syndrome?

What do patients present with?

Back 313

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.

Front 314

314. Gonadotroph adenomas (LH and FSH producing)

Back 314

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.

Front 315

315. What is the morphology of gonadotroph adenomas?

Back 315

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.

Front 316

316. Thyrotroph (TSH-producing) adenomas

Back 316

Thyrotroph adenomas are rare, accounting for approx 1% of all pituitary adenomas.

They are chromophobic or basophilic and are a rare cause of hyperthyroidism.

Front 317

317. Nonfunctioning pituitary adenomas

Back 317

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.

Front 318

318. Do true hormone-negative adenomas really exist?

Back 318

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.

Front 319

319. Clinical presentation of nonfunctioning adenomas

Back 319

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).

Front 320

320. Pituitary carcinomas

What does the Dx require?

Back 320

These tumors are quite rare, and most are not functional.

The diagnosis of carcinoma requires the demonstration of metastasis, usually to lymph nodes, bone, liver, and sometimes elsewhere.

Front 321

321. Hypofunction of the anterior pituitary

Back 321

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.

Front 322

322. Hypopituitarism linked to diabetes insipidus comes from where?

Where do most cases of hypofunction arise from?

Back 322

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.

Front 323

323. Pituitary apoplexy

Back 323

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.

Front 324

324. Ischemic necrosis of the anterior pituitary

What is the most common form?

Back 324

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.

Front 325

325. What causes Sheehan syndrome?

Why is the posterior pituitary not affected?

Back 325

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.

Front 326

326. Rathke cleft cysts

Back 326

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.

Front 327

327. Empty sella syndrome

Back 327

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.

Front 328

328. Primary empty sella

Back 328

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.

Front 329

329. Secondary empty sella

Back 329

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.

Front 330

330. What genetic defects lead to hypopituitarism?

Back 330

Mutations in pit-1, a pituitary transcription factor, results in combined deficiency of GH, prolactin, and TSH.

Front 331

331. What are the two most clinically relevant posterior pituitary syndromes?

Back 331

Diabetes insipidus and SIADH

Front 332

332. ADH deficiency

Back 332

ADH deficiency causes diabetes insipidus, characterized by excessive urination, excessive thirst, and hypernatremia.

Front 333

333. SIADH

Back 333

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.

Front 334

334. What are the most commonly implicated lesions in hypothalamic suprasellar tumors?

Back 334

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.

Front 335

335. Morphology of craniopharyngiomas

What are the two types?

Back 335

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

Front 336

336. Morphology of adamantinomatous craniopharyngiomas

Back 336

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.

Front 337

337. What are three diagnostic features of adamantinomatous craniopharyngiomas?

Back 337

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"

Front 338

338. Morphology of papillary craniopharyngiomas

Back 338

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.