Hypothalamic and Pituitary Relationships Pt. 2 (Lopez)

Question 1

Hormones secreted by adrenal medulla:

Answer 1

• epi and norepi
• catecholamines; rapid response to stress (e.g. hypoglycemia, exercise)

Question 2

Hormones secreted by adrenal cortex:

Answer 2

• cortisol: steroid (glucocorticoid); longer-acting stress response hormone, regulates glucose utilization and immune/inflammatory homeostasis
• aldosterone: steroid (mineralocorticoid); regulates salt/volume homeostasis
• DHEAS: steroid; androgen precursor

Question 3

Describe the HPA axis in terms of cortisol hormone:

Answer 3

• hypothalamus produces/releases CRH (in reponse to stress/circadian rhythm)
• CRH activates production/release of ACTH in anterior pituitary
• ACTH activates production/release of cortisol in adrenal cortex into circulation
• cortisol leads to: immune suppression, gluconeogenesis (liver), protein metabolism (liver), lipolysis (adipose tissue)
• cortisol inhibits: ACTH prod in ant pit and CRH prod in hypothalamus

Question 4

Where is cortisol produced in the adrenal cortex and how is it regulated?

Answer 4

• produced in zona fasciculata
• negative feedback system occurs with cortisol inhibiting production of ACTH in ant pit and CRH in hypothalamus

Question 5

What patterns of secretion does cortisol follow?

Answer 5

• secreted in response to stress: physical (surgery), emotional (fear), metabolic (acute hypoglycemia), infection/inflammation (cytokines)
• also controlled by circadian rhythm: secretory rates of cortisol are high in early morning but late in the evening

Question 6

What are the physiological consequences of glucocorticoid (cortisol) excess?

Answer 6

Question 7

What effects do exogenous glucocorticoids have on the body?

Answer 7

• exogenous (outside of the body) glucocorticoids have the same negative feedback effect as cortisol
• overuse may cause atrophy of adrenal cells that produce cortisol
• examples: Prednisone, Methylprednisone, Dexamethasone

Question 8

• condition caused by high levels of cortisol for prolonged periods of time
• can be caused by: exogenous glucocorticoid (cortisol) excess, pseduo-syndrome, pituitary tumor or ectopic-ACTH tumor (high levels of ACTH), adrenal tumor (high levels of cortisol), or primary adrenal hyperplasia (high levels of cortisol, low levels of ACTH)
• sx: truncal obesity, moon face, “buffalo hump” of back, easy bruising, purple striae of abd, htn, edema, weakness, osteoporosis, hirsutism, acne, diabetes, immunosuppression, cognitive effects

Answer 8

cushing’s syndrome

Question 9

What are the 4 etiologies involving Cushing’s syndrome?

Answer 9

• exogenous glucocorticoid (cortisol) excess (latrogenic)
• pseudo-Cushing’s syndrome: major depression, anxiety, acute/chronic illness (e.g. severe bacterial infection), alcoholism (rare)
• ACTH-dependent: Cushing’s disease (pituitary tumor, most common of ACTH-dep), ectopic-ACTH secreting tumors, CRH-secreting tumors
• ACTH-independent: adrenal adenoma, adrenal carcinoma (secreting high levels of cortisol)

Question 10

How does the dexamethasone suppression test work?

Answer 10

• low-dose: differentiates patients w/ CS (of any cause) w/ patients who do not have CS; no ACTH suppression indicates CS b/c the overprod of ACTH by pituitary tumor is not as sensitive to suppression by corticosteroid as normal functioning ACTH prod pituitary would be; test does not specify source of ACTH over-prod
• high-dose: distinguishes patients w/ CS (either caused by pituitary ACTH-secreting tumor OR caused by ectopic tumor (either ACTH or cortisol secreting)); used after dx of CS is made

Question 11

How is aldosterone regulated?

Answer 11

• decreased Na+ or increased K+ in blood directly stim zona glomerulosa of adrenal cortex to produce/release aldosterone
• decreased blood volume and/or blood pressure indirectly stim kidney to produce/release renin that initiates a cascade of reactions producing angiotensin II
• angiotensin II from kidneys stim zona glomerulosa of adrenal cortex to produce/release aldosterone
• aldosterone activates kidneys to increase Na+/H2O absorption and K+ secretion
• this leads to increased blood volume and blood pressure

Question 12

How does aldosterone increase renal Na+ reabsorption?

Answer 12

1. aldosterone enters P cell of distal nephron and combines w/ cytoplasmic receptor
2. hormone-receptor complex initiates transcription in nucleus
3. translation and protein syn makes new protein channels and ATP pumps
4. aldosterone-induced proteins modulate existing channels/pumps
5. results in increased Na+ reabsorption and K+ secretion

Question 13

Describe primary adrenal insufficiency:

Answer 13

• hypothalamic CRH and ant pit ACTH secretion are normal
• decreased secretion of cortisol and aldosterone from adrenal cortex

Question 14

Describe secondary and tertiary adrenal insufficiency:

Answer 14

• secondary: decreased ant pit production/release of ACTH, causes decreased production of cortisol from adrenal cortex; however, renin/angiotensin system is still intact, thus aldosterone production is normal
• tertiary: decreased hypothalamic prod/release of CRH, causes decreased ant pit ACTH and decreased production of cortisol from adrenal cortex; however, renin/angiotensin system is still intact, thus aldosterone production is normal

Question 15

• an autoimmune disease that causes primary adrenal insufficiency
• can be caused by: adrenal hemorrhage (causes include Waterhouse-Friedrichsen syndrome: hemorrhage secondary to N. meningitidis; or anticoagulant tx); infection (tuberculosis, N. meningitidis); or tumor metastases to adrenal gland
• sx: hypoglycemia; anorexia, weight loss, nausea, vomiting; weakness; hypotension; hyperkalemia; metabolic acidosis; decreased pubic/axillary hair in females; hyperpigmentation

Answer 15

Addison’s disease

Question 16

What causes hyperpigmentation in Addison’s disease?

Answer 16

• ACTH primarily plays a role in activating prod of adrenocorticoids, however at supraphysiological levels it activates prod of alpha-MSH which leads to melanin synthesis
• ACTH has low-affinity binding for MC1R on melanocytes, once it binds it activates PKA which increases melanin synthesis/dispersal, leading to skin darkening
• at the same time, UV light exposure in keratinocytes leads to increased POMC expression (precursor for ACTH), leading to increased production of alpha-MSH
• alpha-MSH has a high-affinity when binding to MC1R, thus hyperpigmentation occurs

Question 17

How is cosyntropin (synthetic ACTH) stimulation test used to detect adrenal gland insufficiency?

Answer 17

Question 18

How is adrenal insufficiency treated?

Answer 18

• usually be replacing the hormones that adrenal glands are not making: cortisol is replaced w/ corticosteroid (hydrocortisone, prednisone, dexamethasone) and aldosterone is replaced w/ the mineralocorticoid, fludrocortisone
• people w/ secondary adrenal insufficiency maintain aldosterone prod, so they do not require mineralocorticoid replacement

Question 19

Differential dx chart of cortisol excess/deficiency:

Answer 19

Question 20

• primary: excessive release of aldosterone fom adrenal cortex (Conn’s syndrome: adenoma in adrenal cortex)
• secondary: excessive renin secretion by juxtaglomerular cells in kindey
• tx: surgery, spironolactone

Answer 20

hyperaldosteronism

(focus on the test for primary aldosteronism)

Question 21

• destruction of the adrenal cortex causes defects in aldosterone synthesis
• inadequate stimulation of aldosterone secretion

Answer 21

hypoaldosteronism

Question 22

How are steroids synthesized by the adrenal cortex?

Answer 22

*cholesterol > (cholesterol desmolase, rate limiting step) > pregnenolone*

• aldosterone (zona glomerulosa): pregnenolone > (3β) > progesterone > (21) > 11-DOC > (11) > corticosterone > (18) > 18-OH corticosterone > (18-oxidase) > aldosterone
• cortisol (zona fasciculata): pregnenolone > (3β) > progesterone > (17α) > 17-OH progesterone > (21) > 11-deoxycortisol > (11) > cortisol
• androgens (zona reticularis): pregnenolone > (17α) > 17-OH pregnenolone > (17,20) > DHEA > (3β) > androstenedione (minor product)

Question 23

How is the mineralocorticoid receptor protected from activation by cortisol?

Answer 23

• the enzyme 11β-HSD2 protects mineralocorticoid receptor activation by cortisol, which would cause amplication of the aldosterone pathway
• this enzyme converts cortisol into cortisone
• cortisone is shuttled back into BS where it can enter into back into the cortisol pathway by being converted back into cortisol but 11β-HSD1

Question 24

What are all congenital adrenal enzyme deficiencies characterized by?

Answer 24

• adrenal hyperplasia
• enlargement of the adrenal glands is caused by increased ACTH stimulation due to low cortisol levels

Question 25

• unilateral adrenal medulla tumor, usually benign
• rare, but extremely dangerous cause of hypertension
• cathecholamines secreted by this tumor stimulate both alpha and beta adrenergic receptors
• sx: hypertension, headaches, palpitations, sweating
• dx confirmation: by elevated levels of catecholamines and their metabolic products

Answer 25

pheochromocytoma

Question 26

How does sympathetic system regulate catecholamine synthesis?

How does cortisol add to this regulation?

Answer 26

• sympathetic system: stimulation of this system leads to release of NT, ACh, which stimulates the conversion of tyrosine > XDOPA (by tyrosine hydroxylase) and dopamine > norepi (by dopamine- β-hydroxylase)
• cortisol upregulates phenylethanolamine-N-methyl transferase (PNMT) enzyme, which converts norepi to epi

Question 27

What is the signal for catecholamine secretion from the adrenal medulla?

Answer 27

acetylcholine

Question 28

How are the catecholamines synthesized?

Answer 28

(occurs in different cellular compartments)

• cytoplasm: tyrosine > (tyrosine hydroxylase, rate limiting step) > L-DOPA
• cytoplasm: L-DOPA > (AADC) > dopamine > dopamine transported into secretory vesicle (chromaffin granule)
• granule: dopamine > (DBH) > norepi > almost all norepi diffuses out of granule by facilitated transport
• some norepi is package into secretory vesicles (chromaffin granules)
• cytoplasm: some norepi > (methylated by PNMT) > epi
• epi transported back into granule by VMATs
• multiple molecules of epi, and lesser amnts of norepi are stored in chromaffin granule w/ ATP, Ca2+, and chromogranins
• hormones are eventually secreted out via exocytosis

Question 29

How are catecholamines degraded?

Answer 29

• epi and norepi can be converted to dihydroxymandelic acid by monoamine oxidase (MAO)
• dihydroxymandelic acid then coverted to vanillylmandelic acid (urine) by COMT
• epi and norepi can be converted to metanephrine and normetanephrine respectively by catecholamine-O-methyltransferase (COMT) and then by MAO to vanillylmandelic acid (urine)

Question 30

What are the catecholamine receptors?

Answer 30

Question 31

What are the major physiological actions of catecholamines?

Answer 31

Question 32

Describe the actions of epi vs norepi in differing amnts:

Answer 32

Question 33

Describe the HPA stress response in terms of short-term and long-term stress:

Answer 33