Flashcards in Unit 6 - Adrenal and Supradrenal gland Deck (34)
what is the adrenal cortex derived from? what does it secrete? what does it mean by "essential"?
-derived from mesoderm
-secretes glucocorticoids/androgens from zona fasciculata and reticularis, and mineralccorticoids from zona glomerulosa
-essential b/c total loss of funcction is fatal in 4-14 days
what is adrenal medulla derived from? what does it secrete? is it essential for life?
-derived from neural crest
-secretes E, NE, dopa, dopamine
-modified post-ganglionic sympathetic nerve cells
-total loss is not life-threatening
what is the rate-limiting reaction in steroid hormone synthesis?
cholesterol to pregnenolone via 20,22 desmolase (AKA P450 side-chain cleavage enzyme)
how many enzymes in the "steroid hormone forming" pathway are of the P450 family?
all of them except cytosolic 3-beta hydroxysteroid dehydrogenase
is there a storage pool of aldosterone? what happens once it's secreted?
no, since it's a steroid hormone
-secretion is limited by the rate at which glomerulosa can synthesize the hormone
-once secreted, 37% are free in the plasma, and the rest weakly binds to CBG and albumin
what is the major action of aldosterone?
-stimulate kidney (distal nephron segments) to reabsorb sodium and water, and enhance potassium secretion
--similar actions in colon, salivary glands, and sweat glands
-increases activity of Na/K pump and expression of apical Na channels
what enzyme does the glomerulosa layer lack that the fasciculata and reticularis have?
it doesn't have 17-alpha-hydroxylase, which is found in the SER of all other adrenal cortex layers
-so once it's made in the other 2 layers, corticosterone can be moved to mitochondria of glomerulosa to be converted to aldosterone via aldosterone synthase
what enzyme does the fasciculata and reticularis lack that the glomerulosa has?
they don't have aldosterone synthase, but they have 17-alpha-hydroxylase
-they also don't have 17-keto-dehydrogenase, so androstenedione must be moved to testes to be converted to testosterone
cortisol transport in plasma
90% bound to cortisol binding PRO (CBP or transcortin)
7% to albumin
3% is "free"
androgen synthesis in adrenal gland
-how strong are they?
-when do they peak?
DHEA (dehydroepiandrosterone) and androstenedione are major adrenal androgens
-less potent than testosterone or dihydrotestosterone, but androstenedione can be converted to testosterone in peripheral tissue
-peak in 20's, decline in early 30's (75 yo has 20% of a 25 yo)
--important for maintaining sex drive in females after menopause
how does cortisol work once inside the cell?
1. 'free" cortisol enters target cell by diffusion
2. binds to cytoplasmic receptor associated with heat shock proteins
-cytoplasmic activation creates active GR monomer, which then dimerizes
3. migrates to nucleus and enters as dimer
4. modulates gene transcription via GRE
what does cortisol inhibit via feedback inhibition loop?
-anterior pituitary: POMC expression, release of premade ACTH, expression of CRH receptor
-hypothalamus: decreases mRNA and peptide levels of CRH, and release of premade CRH
what are metabolic effects of cortisol action?
-stimulate gluconeogenesis in liver
-enhance PRO breakdown in muscle to provide AA substrate for gluconeogenesis
-stimulate lipolysis in adipose in periphery as alternative to glucose
--for some reason, fat is deposited centrally and on face
-decreases osteoplastic activity in trabecular bone, and interferes with Ca++ absorption in gut
-decrease GLUT in most tissues except brain to block glucose uptake
what are anti-inflammatory effects of cortisol action?
-inhibits cytokine production
-inhibits chemo-attractant molecule production
-stabilizes lysosomal enzymes
-contributes to vasoconstriction and decreased capillary permeability
what are immunosuppressive and neural effects of cortisol action?
-decreases lymphocyte proliferation
-inhibits hypersensitivity reactions (especially cell-mediated)
--inhibits IL (especially IL-2) and receptor expression
-emotional instability (receptors are in brain)
immunosuppressive effects usually at high doses
how do glucocorticoid VS mineralocorticoid potency differ?
if something has good glucocorticoid potency, it generally has weaker mineralocorticoid potency, and vice versa
what is the most important regulator of cortisol?
what does prolonged PKA expression in adrenal cortex cells do?
has ACTH-like effects
how does CRH bind to receptor?
-what happens if it binds
-what happens if it is prolonged/
CRH is 41-AA neuropeptide made in paraventricular nucleus of hypothalamus
-CRHR are GPCR on cell membrane of corticotrophs
-hormone binding activates signaling thru second messengers for increased [Ca++] and exocytosis of preformed ACTH
-prolonged CRH receptor activation leads to increased gene transcription and synthesis of ACTH precursor
how does ACTH bind to receptor?
-what happens when it binds, and if prolonged?
ACTH is 39-AA peptide hormone made by corticotrophs of anterior pituitary
-made by post-translational processing of preprohormone (POMC)
-ACTHR is GPCR called melanocortin-2 receptor
-increased cAMP activates PKA, which phosphorylates many PRO
-rapid effect is to stimulate rate-limiting step in cortisol formation (20,22 desmolase for cholesterol --> pregnenolone)
-prolonged increases synthesis of PRO involved in cortisol synthesis
how is ACTH processed? in anterior pituitary VS intermediate pituitary?
post-translational processing of POMC
-AP: makes ACTH and beta-LPH (lipotropin)
-IP: makes alpha-MSH (anoxygenic hormone) and beta-endorphin (among other things; usually done in fetal life and pregnancy)
how is cortrisol secretion related to the circadian rhythm?
diurnal variation with highest levels in early morning, and lower levels in evening
-info about light/dark cycle is transmitted from retina to suprachiasmatic nucleus of hypothalamus that controls circadian rhythms of body
-CRH release is in pulses, causing ACTH in pulses
-thus, rhythmic ACTH directly controls diurnal variation of cortisol production
how is cortisol secretion and stress related?
physical, psychological, and biochemical stress enhance CRH secretion, thus enhanced ACTH secretion, thus more cortisol
-this happens in hypoglycemia, which then raises blood glucose levels
21-alpha-hydroxylase deficiency symptoms
most common form of congenital adrenal hyperplasia (1:7000)
-decreased aldosterone synthesis
--loss of salt, hypotension, dehydration
-decreased cortisol synthesis
--hypoglycemia, adrenal hyperplasia (since increased ACTH due to no negative feedback from cortisol)
-increased androgen production
--ambiguous genitalia in females, virilizing effect in males
21-alpha-hydroxylase deficiency diagnosis and treatment
-have elevated 17-hydroxyprogesterone before and after ACTH stimulation test
--diagnosis should be confirmed by molecular genetic analysis of CYP21 gene
-provide glucocorticoids (prednisolone, dexamethasone) to replace cortisol and reduce ACTH (which also reduces hyperplasia and androgen overproduction) and mineralcorticoids (fludrocortisone) to prevent salt-wasting or increased renin
17-alpha-hydroxylase deficiency symptoms
increased aldosterone synthesis
decreased cortisol synthesis
-hyperplasia of adrenal gland (but no hypoglycemia, because increased corticosterone can provide enough)
decreased androgen synthesis
-sexual infantilism in both, pseudohermaphroditism in males
-deccreased estrogen synthesis in ovary
17-alpha-hydroxylase deficiency treatment
-HTN and mineralocorticoid excess treated with glucocorticoid replacement
-genetic females given estrogen
-genetic males given surgery or testosterone treatment
Cushing syndrome VS disease
syndrome: excess cortisol of any etiology
-hypercortisolism or hyperadrenocorticism
disease: only hypercortisolism secondary to excess production of ACTH from pituitary gland adenoma
what are some causes of Cushing's syndrome?
-prolonged use of immunosuppression drugs (prednisone)
-things that increase ACTH like pituitary adenomas (Cushing's disease) or ectopic ACTH syndromes