Week 2: Overview of Hypothalamic-Pit regulation & Adrenal function

Question 1

Primary dysfunction

Answer 1

-if abnormal level of a hormone arises from a dysfunction in the peripheral gland making the hormone

Question 2

Secondary dysfunction

Answer 2

• If the cause of the abnormal hormone level arises from a pathology in the pituitary, the hypothalamus, or elsewhere
• may see inappropriate relationship: e.g. if hormone from peripheral gland is abnormal and level of pituitary hormone promoting its release is in normal range.

Question 3

Organization of the adrenal gland

Answer 3

CORTEX
1. glomerulosa --mineralocorticoids
-aldosterone
2. fasciculata-- glucocorticoids
-cortisol
3. reticularis
-androgens
MEDULLA --catecholamines

Question 4

Adrenal medulla and catecholamines

Answer 4

• predominantly epinephrine (derived from tyrosine)
• released in response to sympathetic stimulation
• epinephrine have higher affinity for beta receptors, but response is based on tissue ratio of alpha and beta receptors
• physiological levels cause vasodilation, pharmacological can stimulate alpha receptors to cause vasocontriction
• also makes NE, but not significant. Nerve terminals are major source of NE.

Question 5

Synthesis of steroid hormones by adrenal cortex

Answer 5

• make from cholesterol
• C19 steroids are androgenic
• C21 steroids with 2-C chain attached to position 17 are glucocorticoids and mineralocorticoids
• adrenal gland doesn’t store steroid hormones, they are released soon after synthesis

Question 6

Adrenal androgens

Answer 6

• DHEA and androstenedione produced by zone reticularis
• have weak androgenic activity
• for females, peripheral conversion of these hormones to testosterone has effects (hirsutism)
• in males, testicular production of testosterone is much greater

Question 7

Adrenal mineralocorticoids

Answer 7

• AngII is major stimulator of synthesis and release of aldosterone
• secreted by zone glomerulosa.
• primary regulation through renin-angiotensin II-aldesoterone system and via K+ levels

Question 8

Adrenal glucocorticoids- circulation

Answer 8

• Cortisol and cortisone released from fasciculate zone of adrenal gland
• circulate bound to transcortin (a2 globulin)
• the free forms of hormones are active

Question 9

mechanisms determining specificity of glucocorticoid actiosn

Answer 9

• Type 1 receptors have mineralocorticoid actions
• Type 2 have glucocorticoid response
• Type 1 have equal affinity for cortisol and aldosterone
• 11b-hydroxy-steroid dehydrogenase converts cortisol and corticosterone but not aldosterone to forms (cortisone and 11-dehydrocorticosterone) that bind poorly to Type 1 and 2 receptors
• 11bHSD1: in most tissues, increases glucocorticoid action by converting cortisone to cortisol
• 11bHSD2: converts cortisol to cortisone in aldosterone target tissues such as kidney, colon, sweat glands

Question 10

Actions of glucocorticoids

Answer 10

1. stimulation of gluconeogensis
   - overall: catabolic and diabetogenic
   - promotes storage of glucose in liver as glycogen during absorptive state
   - increases protein catabolism in muscle, decreases new protein synthesis
   - increases lipolysis, provides glycerol to liver
   - decreases insulin sensitivity of adipose tissue
   - essential for fasting and survival of stress
2. Anti-inflammatory effects
   - induces synthesis of lipocortin, which inhibits phospholipase A2
   - inhibits production of Il-2 and proliferation of T lymphocytes
   - but can impede the walling off of infection
3. maintenance of vascular responsiveness to catecholamines
   - lack of leads to capillary dilation and excessive permeability
4. Inhibition of bone formation
5. increases GFR by vasodilation of afferent arterioles
6. effects on CNS

Question 11

Regulation of cortisol secretion

Answer 11

• pulsatile release
• main regulator: pituitary ACTH (adrenocorticotropic hormone)
• ACTH increases adrenal cAMP
• controlled by negative feedback, inhibited by circulating steroids
• chronic Rx with GCs leads to ACTH suppression and atrophy of adrenal gland
• CRH stimulates ACTH release. negative feedback with cortisol.

Question 12

Cushing disease and syndrome

Answer 12

• syndrome: GC excess from any case
• disease: elevated ACTH e.g. from pituitary tumor
• possibly from activating mutations in cAMP dependent protein kinase
• HTN, muscle weakness, central obesity, fat in face and behind neck
• compromised collagen synthesis leading to striae