Endocrinology Test 2

Front 1

What are the two regions of the hypothalamus and what are their released hormones?

Back 1

1. Hypothalamic hypophyseal tract - Release of oxytocin and ADH to posterior pituitary (Neurohypophysis)

2. Hypothalamic hypophyseal portal system - releases 7 hormones to target cells in anterior pituitary (adenohypophysis)

Front 2

What happens to the nine hormones released by the hypothalamus?

Back 2

They are released to the pituitary gland via the INFUNDIBULUM (pituitary stalk) which connects the glands

Front 3

What is the hypothalamus?

Back 3

a. Contains several nuclei (clusters of neuronal cell bodies) that regulate autonomic functions in the body, located in the brain region called diencephalon. The hypothalamus is located below the thalamus

Front 4

What synthesizes ADH and Oxytocin?

Back 4

Two hypothalamic nuclei called:
1. Paraventricular nuclei
2. Supraoptic nuclei

Front 5

What are the stimuli for the release of ADH?

Back 5

1. Hypovolemia - DECREASED blood volume as it may occur in hemorrhaging (blood loss)

2. INCREASED blood osmolality due to dehydration or INCREASED in salt intake

Front 6

What are the ADH receptors?

Back 6

V1 receptors - Uses the PIP signal transduction mechanism. When ADH binds to V1 dissociation of Gqa

V2 receptors - Uses signal transduction mechanism. When ADH binds to V2 dissociation of Gsa

Front 7

What are the biological effects of ADH?

Back 7

1) ADH binds to V1 receptors on the smooth muscle cells in blood vessel walls which leads to vasoconstriction

2) ADH stimulates the release of clotting factors from the liver. These clotting factors stimulate blood clot formation or blood coagulation. This seals off the damaged blood vessel to prevent further blood loss

3) ADH stimulates the thirst center in the hypothalamus to stimulate water intake

4) ADH binds to the V2 receptors on the cells in the distal convoluted tubules (DCTs) and the collecting ducts to stimulate water reabsorption

Front 8

What are the possible causes of diabetes insipidus?

Back 8

1. Neurogenic (central DI) = (Sensitive ADH DI)
2. Nephrogenic DI (=insensitive ADH DI)

Front 9

What are the causes of neurogenesis?

Back 9

1. Damage to the supraoptic and paraventricular nuclei in the HYPOTHALAMUS due to head injury, infection, or autoantibodies (autoimmune disease) that destroy these nuclei
2. Damage to the hypothalamic hypophyseal tract (Delivery system is destroyed)
3. HYPOPHYSECTOMY  surgical remove of the pituitary gland (hypophysis due to malignancy --CANCER)

Front 10

What are the causes of nephrogenesis?

Back 10

1. Damage or inadequate V2 receptors on the cells in the DCT and the collecting duct

2. May also be due to PYELONEPHRITIS: Destroys the concentration between the medullary interstitium and the DCT/collecting duct

3. X-linked genetic condition which causes a decrease in the V2 receptors

Front 11

What are the signs/symptoms of Diabetes Insipidus (Both Neurogenic and Nephrogenic)

Back 11

1.Copious amounts of DILUTED URINE--INCREASED urine volume--DECREASED urine osmolarity

2.Blood--DECREASED blood volume--INCREASED blood plasma OSMOLALITY

Front 12

How can you run a diagnostic test for DI?

Back 12

1.Measure the urine volume/osmolality and blood volume/osmolality (check to see if DI is suspected)

2.Measure ADH levels in the blood (Low = neurogenic) (High ~ nephrogenic)

3.Vasopressin test – giving synthetic ADH (desmopressin acetate)

4. If the urine volume decreases upon ADH addition (neurogenic DI confirmed) OR If levels remain unchanged (nephrogenic DI confirmed)

Front 13

What are the causes of SIADH?

Back 13

syndrome of inappropriate ADH secretion
1. Brain (head injury)
2. Tumors of the hypothalamic nuclei involving the paraventricular and the supraoptic nuclei
3. Ectopic production of tumors of other organs

Front 14

What are the signs/symptoms of SIADH and how may one manage it?

Back 14

1. Blood--INCREASED blood volume--DECREASED blood osmolality
2.Urine--DECREASED urine volume--INCREASED urine osmolality

Treat with
1) Water restriction
2) diuretics to INCREASE urine output

Front 15

What is oxytocin?

Back 15

nonapeptide released from the posterior pituitary via NEUROENDOCRINE REFLEX (neural stimulus)

Front 16

What are the stimuli for oxytocin release?

Back 16

1. The vagina is stimulated. Stimulation of the vagina to release oxytocin is termed the FERGUSON REFLEX
2. Suckling of the nipples of the breasts. During these stimulations, nerve impulses are sent to the hypothalamus (for oxytocin synthesis) and to the posterior pituitary for oxytocin release into the blood stream to reach its targets

Front 17

What are the targets of oxytocin?

Back 17

1. Smooth muscle cells of the myometrium (middle layer of uterine wall)
2. Myoepithelial cells surrounding the alveoli and the lactiferous ducts in the breasts

Front 18

What is the mechanism of action for oxytocin?

Back 18

Oxytocin binds to activation receptors to cause the activation of Gqα (PIP signal transduction mechanism)

Oxytocin stimulates the smooth muscle contraction of the myometrium during PARTURITION (labor) to expel the fetus

Oxytocin binds to its receptors on myoepithelial cells to cause contraction and a “squeezing” effect on the alveoli (alveolar glands = secreting glands) to release milk into the lactiferous ducts

Front 19

What are the cell types of the anterior pituitary?

Back 19

1) Somatotrophs
2) Lactotrophs
3) Thyrotrophs
4) Corticotrophs
5) Gonadotrophs

Front 20

What is growth hormone?

Back 20

191 peptide hormone released produced and released by somatotrophs. Cleavage of prohormone produces active form of hormone. Binds to GH receptors on the surface of target cells to stimulate the JAK-STAT pathway.

Front 21

What are eight stimuli for GH release?

Back 21

1. GHRH - hypothalamic peptide hormone that uses cAMP dependent signal transduction mechanism to stimulate synthesis
2. Sleep - 70% of daily GH occurs during third stage of non-REM sleep
3. Hyperaminoacidemia - HIGH levels of amino acid in blood occuring after meal (postprandial)
4. Hypoglycemia - DECREASE in glucose levels in blood
5. a-adrenergic receptor agonist (ex. Clonidine)
6. B-adrenergic receptor antagonist (ex. propranalol)
7. Dopamine agonists (except in acromegaly where dopamine would inhibit GH release)
8. Starvation/anorexia leads to severe hypoglycemia

Front 22

What are six factors that would inhibit GH release?

Back 22

1. GHIH - aka Somatostatin 14 - utilizes cAMP dependent Gia
2. Hyperglycemia
3. Hyperlipidemia
4. a-adrenergic receptor antagonist
5. B-adrenergic receptor agonist
6. Obesity which leads to hyperglycemia and hyperlipidemia from overeating

Front 23

What are the direct effects of GH?

Back 23

1. Directly breaks down fats (triglycerides) via a catabolic process known as LIPOLYSIS
2. Stimulates hepatocytes (liver cells) to produce SOMATOMEDINS (IGF 1 and 2)

Front 24

What are the indirect effects of GH?

Back 24

1. INCREASE in cellular uptake of amino acids, decreases blood levels of amino acids
2. INCREASES glucose levels in blood by antagonizing insulin in the stimulation of GLUTs
3. Stimulates the release of glucocorticoids (ie. cortisol) through a permissive effect to INCREASE gluconeogenesis
4. GH via IGF1/IGF2 stimulates longitudinal bone growth

Front 25

How does GH stimulate growth?

Back 25

Growth hormone causes linear bone growth INDIRECTLY by GH stimulating the production of IGF by hepatocytes. IGF binds to IGF receptors on the cartilage cells (chondrocytes) to stimulate the proliferation of chondrocytes on the epiphyseal phase of the epiphyseal plates.

Front 26

What is OSSIFICATION?

Back 26

When epiphyseal plate is turned into bone tissue and extension of the diaphysis ceases. Referred to as epiphyseal plate closure and final height is determined

Front 27

How is bone elongated?

Back 27

• Cartilage is added onto the epiphyseal face of the epiphyseal plates. The same amount of cartilage added  will be converted to bone tissue on the diaphyseal face of the epiphyseal plate, shifting the epiphyseal plates as the diaphysis lengthens.

Front 28

How does bone growth stop?

Back 28

• In late adolescence to early adulthood, the levels of growth hormone decrease (childhood-adolescence = 700 ug/day of growth hormone); adulthood = 400 ug/day

• Hence, the rate of chondrocyte proliferation and the addition of cartilage on the epiphyseal face decreases, and it is outpaced by the rate of ossification on the diaphyseal face.

Front 29

What are the causes of DWARFISM?

Back 29

Hypofunction of GH
1.DECREASE in GHRH from hypothalamic neurons
2. DECREASE in number of somatotrophs (Normal levels = 50% all cells in anterior pituitary are somatotrophs)
3. Insensitive GHRH receptors on somatotrophs
4. in biosynthetic pathway for GH
5. Receptor defect of GH receptors on target cells = result in a specific type of dwarfism called LARON’S SYNDROME or LARON’s DWARFISM
a. HIGH levels of GH
b. Negligible levels of IGF

Front 30

What are the characteristics of dwarfism?

Back 30

1. Short stature
2. Obesity due to absence of lipolytic effect of GH => results in DECREASE in GH release due to hyperglycemia/hyperlipidemia
3. HYPOGLYCEMIA associated with dwarfism due to hyperfunction of GH because GH is a DIABETOGENIC hormone à GH INCREASES blood glucose levels
4. HYPOGLYCEMIA, when severe is associated with seizures à NEURONS (including the brain use glucose exclusively to generate energy)
5. Hence, hypoglycemia à DECREASE glucose delivery to brain tissue à seizure activity
6. Child-like facial appearance, high-pitched voice
. ***Obesity may be due to overeating OR due to growth hormone hypofunction, one must look at the glucose levels to determine this. (QUESTION ASKED after class)

Front 31

What is the OVERNIGHT Fasting test?

Back 31

Test in dwarfism - without any food, you are presenting the system with hypoglycemia and we know that 70% of GH is released during sleep

Normal individual has about 50 ug/ml GH in blood while afflicted has less than 2ug/ml in blood.

In individuals with Laron's dwarfism or the congenital inability to produce IGF by hepatocytes you will see INCREASE in GH levels after overnight fast (higher than normal because in both scenarios, IGF is absent. High levels of IGF will exert a negative feedback on GH release

Front 32

What is the levadopa challenge test?

Back 32

Test for GH deficiency, L-DOPA = dopamine agonist

1. Measure GH levels in blood after administering Levodopa = If GH levels are still low/negligible, suggests Dwarfism due to GH deficiency
Dopamine agonists stimulate GH release

Front 33

What is the arginine test?

Back 33

Diagnostic test for dwarfism, infuse arginine to create hyperaminoacidemia (strong stimulus for GH release). Measure GH levels in the blood, If low/negligible, confirmed GH deficiency

Front 34

What is the insulin challenge test and why must it be under medical supervision?

Back 34

-Give insulin to stimulate glucose uptake by insulin-dependent cells
-Neurons, which are not insulin dependent (only picks up glucose based on concentration gradient) will NOT be capable of taking in glucose = neurons deprived of glucose = not functional resulting in hypoglycemic coma = death
-If the GH levels in blood are still low/negligible after insulin challenge test = confirmed dwarfism due to GH deficiency
-Must prevent hypoglycemic shock => hypoglycemic coma => DEATH

Front 35

What is hyperfunction of GH termed in childhood and adulthood?

Back 35

Childhood = Gigantism
Adulthood = Acromegaly

Front 36

What are the causes of hyperfunction of GH?

Back 36

1. Hypothalamic tumors -> INCREASE in GHRH
2. Ectopic site production of GHRH
3. Tumor of the pituitary involving the somatotrophs = INCREASE GH
4. Ectopic site production of GH

Front 37

What are the characteristics of gigantism?

Back 37

Accelerated growth of long bones, leading to excessive heights above 7 feet tall (limbs are longer for size of trunk). Excessive growth of the flat bones of the skull leads to broad foreheads.
Increased muscle mass and Increased connective tissue leads to bulky appearance

Front 38

What are the characteristics of acromegaly?

Back 38

-Occurs AFTER epiphyseal plate closure
1. POSITIONAL bone growth which INCREASES bone diameter (not length)
2. INCREASE in facial bone growth results in SPLAYED teeth (widely spread) - Facial bones most affected, widening of the face. Mandible grows forward and downward (prognathism)
3. INCREASE in muscle mass
4. INCREASE in connective tissue
5. INCREASE in weight gain
6. INCREASE in growth of phalanges
7. Sebaceous (oil) glands and the suderiforous glands are INCREASED by high levels of GH causeing acne and hyperhidrosis (excessive sweat)
8. Diabetes mellitus = INCREASE in glucose levels in blood due to diabetogenic effect of GH
9. Persistent hyperglycemia caused by GH results in hyperinsulinemia
10. Present with renal calculi (kidney stones)

Front 39

How does acromegaly cause renal calculi?

Back 39

High levels of GH stimulate 1-a-hydroxylase, which is required for the production of active Vitamin D = Increase in calcium absorption from small intestine into blood.
-In the presence of PTH, VitD will synergize with PTH to cause bone resorption and add INCREASED Ca2+ tubular fluid in kidneys => INCREASE in renal calculi formation

Front 40

How does acromegaly cause cardiovascular problems?

Back 40

1. INCREASE GH stimulates formation of LDL (bad cholesterol) = Formation of plaques in blood vessels = atherosclerotic plaques = INCREASED resistance and BP = hypertension = cardiomegaly, and increase in size causes thin and thick filaments to NOT overlap and cardiac muscle contraction is compromised
2. High levels of GH directly stimulates cardiomegaly (cardiac muscle growth)

Front 41

What diagnostic tests are taken for acromegaly?

Back 41

1. Glucose suppression test = give 100g of glucose and measure GH levels in blood an hour later
i. If acromegaly, GH levels will be high
ii. If NO acromegaly, GH levels will be very low since hyperglycemia inhibits GH release
2. TUMOR LOCALIZATION using MRI
i. If caused by pituitary tumor = headaches, visual disturbances. If benign adenoma, remove through trans-sphenoidal microsurgery to reach Sella turcica (cradles pituitary gland)
About 90% of acromegalics will have pituitary adenoma)
If tumor is located in hypothalamus (INCREASE GHRH) or ectopic tumor that is inoperable, use Somatostatin analog called OCTREOTIDE