Flashcards in Medical Physiology Block 7 Week 1 Deck (86):
What are the endocrine glands?
pituitary, thyroid, parathyroid, testes, ovary, the adrenal cortex and medulla, and endocrine pancreas
Name the paracrine factors.
interleukins, lymphokines, PDGF, FGF
What is the main neuropeptide?
somatostain released from pancreas and hypothalamus
Name the peptide hormones.
pancreas: insulin, glucagon, and somatostain
pituitary: growth hormone, gonadotropin hormones (LH and FSH), adrenocorticotropic hormone (ACTH), thyrotropin, and prolactin
hypothalamus: somatostatin and several releasing hormones
What are catecholamines derived from? steroid hormones?
What cells in the anterior pituitary can secrete more than one hormone?
gonadotropin-producing cells (FSH and LH)
Which hormones require binding proteins?
thyroid hormones, steroid hormones, IGF-1 and -2, and growth hormone
What is the function of binding proteins in serum?
provides a reservoir or pool of the hormone; extends the half-life of the hormone
Is there a trend that hormones that have a primary action of long term modulation of gene transcription are bound to plasma proteins?
Yes; peptide hormones and catecholamines produce rapid responses and circulate freely
What hormones complement each other during exercise? growth? which hormones have antagonistic actions?
glucagon, epinephrine, and cortisol; GH, insulin, IGF-1, thyroid hormone, and sex hormones; insulin and glucagaon
Describe the anatomy of the pituitary lobe.
highly vascular; Posterior pituitary receives arterial blood, whereas the anterior pituitary receives only portal venous inflow from the median eminence (outside the BBB);
Which hormone secreted by the pituitary has no endocrine feedback mechanism?
How are neurohypophysis hormones synthesized?
produced as prohormones and cleaved during transport along the axons
Is peptide hormone synthesis increased following stimuli that induce secretion?
What is the signaling cascade for glucagon? AVP? TSH? TRH? ANP? insulin? IGF? PDGF? EGF? GH? LIF? erythropoitin? angiotension?
Gs; Gq; Gq; Gq (PLA2); guanylyl cyclase; RTK; RTK; RTK; RTK; tyrosine kinase-associated receptors; same as GH; same as GH; mutliple signaling cascades
Do catecholamines have hierarchic feedback system?
no; controlled by the CNS
What tissues in the body have the capacity to form hormones from cholesterol?
adrenal cortex makes cortisol, aldosterone, and androgen; the gonads make either estrogen and progesterone (ovary) or testosterone (testes)
Do cholesterol-based hormones have cellular storage pools?
Describe steroid receptors.
monomeric phosphoproteins; homology among receptors, particularly C DNA binding domain; dimerize on binding to their target sites on DNA (two zinc fingers)
What are the effects of steroid hormones?
regulate gene transcription; stabilize specific mRNA molecules (increasing half-life)
How do tissues specify the response to steroid hormones?
abundance of specific steroid receptors
genes for steroid receptor proteins do not have steroid response element in their 5' flanking region (gene transcription must occur following hormone binding to receptor; sometimes the receptor is recycled from the nucleus back to the cytoplasm)
Do steroid and thyroid hormones have nongenomic actions?
yes; through PI3K mediated phosphorylation (example: estrogen receptor alpha binds strongly to PI3K stimulating phosphorylation of PIP2 to PIP3 and modulation of NO synthase activity)
Where are the adrenal glands located?
above the upper pole of each kidney in the retroperitoneal space
Describe the anatomy of the adrenal glands.
cortex is derived from mesoderm, whereas the medulla is derived from neural crest cells that migrate into the developing cortex
Describe the adrenal cortex.
glomerulosa layer near surface produces aldosterone, the fasciculata layer in the midcortex produces cortisol, and the reticularis layer near the cortical-medullary junctions also produces cortisol
What are the three major classes of steroid hormones?
glucocorticoids (increase plasma glucose levels), mineralocorticoids (promotes salt and water retention by the kidney), and sex steroids
Does aldosterone at physiological concentrations have glucocorticoid activity? does cortisol have mineralocorticoid activity?
How does the adrenal cortex obtain cholesterol?
imported from circulation via LDL receptor-mediated endocytosis or synthesized de novo from acetate by way of acetyl coA
T/F: Enzymes utilized for conversion of cholesterol to steroid hormone belong to the cytochrome P-450 oxidase family?
True; exception is 3beta-hydroxysteroid dehydrogenase
How is cortisol synthesized?
SCC enzyme removes long side chain on C-20 (rate-limiting step) in the mitochondria producing pregnenolone; the SER enzyme 3beta hydroxysteroid dehydrogenase oxidizes pregnenolone generating a ketone, progesterone; 17alpha-hydroxylase in the SER adds a hydroxyl group; 21alpha-hydroxylase produces 11-deoxcycortisol (SER); 11beta-hydroxylase produces cortisol
Is 17alpha-hydroxylase present in the glomerulosa layer?
What other products can be formed from 17alpha-hydroxylpregnenolone and 17alpha-hydroxyprogesterone? What enzyme is required? Can these products be converted to other hormones?
weak androgens: dehdroepiandrosterone and androstenedione; 17,20 desmolase (17alpha-hydroxylase); yes, peripheral tissue may use 17-ketosteroid reductase to androstenedione to testosterone
How is cortisol transported in blood?
most bound to transcortin (produced in the liver) or albumin (also produced in the liver); less than 5% is free in the circulaton
How is cortisol inactivated? Why is this important in the clinical setting?
SER enzyme 11beta-HSD; 11beta-HSD-1 is reversible meaning that administration of cortisone can produce cortisol; 11beta-HSD-2 irreversibly converts cortisol to cortisone in the kidney
Describe cortisol's actions on target tissue.
binds to glucocorticoid receptor located in the cytoplasm causing the receptor to dissociate from hsp90 (E region of receptor binds cortisol);
in the liver: metabolism of amino acids and gluconeogensis
in muscle: breakdown of muscle protein
in adipose tissue: mobilization of fat
inflammatory response: promotes neutrophil release from marrow into circulation to induce sequestration in the spleen and thymus); at high concentrations, cause lymphocyte lysis
in the bone: decrease the ability of osteoblasts to synthesize new bone (interferes with calcium absorption in the GI tract)
in the CNS: alters mood and cognition
Describe in detail the CRH-ACTH-cortisol axis.
release of CRH is coordinated by CNS stress response and daily circadian rhythms; CRH binds to Gs GPCR (L-type calcium channels and increased intracellular calcium results in ACTH exocytosis and increases ACTH precursor transcription);
Pituitary corticotrophs synthesize ACTH by complex post-translational processing of a large precurose protein (preprohormone) called proopiomelanocortin (POMC)
in the adrenal cortex, ACTH binds to MCR2 (Gs) on the plasma membrane of all three layers of the cortex (increases production of enzymes required for cortisol synthesis)
negative feedback: in the corticotrophs of the anterior pituitary, cortisol acts by inhibiting synthesis of CRH receptor and ACTH (also inhibits the release of presynthesized ACTH stored in vesicles); plasma cortisol decreases the mRNA and peptide levels of CRH in the paraventricular hypothalamic neruons (an inhibits the release of presynthesized CRH)
What is a secretagogue for ACTH?
At what time of day is ACTH secretory activity greatest?
early morning and diminishes in the early evening (increased burst rather than frequency)
What are trophic factors for the fasciculata and reticularis layers of the adrenal cortex? glomerulosa?
ACTH (absence causes atrophy); angiotensin II and high levels of potassium
What has a higher half-life ACTH or cortisol?
REVIEW: what hormone is the primary regulator of extracellular volume? plasma osmolality?
aldosterone; arginine vasopressin (free water balance)
How is aldosterone synthesized?
SCC (rate-limiting step; produces pregnenolone); the SER enzyme 3beta-HSD produces progesterone; 21alpha-hydroxylase produces 11-doxycorticosterone (DOC); aldehyde synthase (18 methyloxidase; hydroxylase and dehydrogenase activity) produces aldosterone
What are secretagogues for aldosterone?
extracellular potassium, angiotensin II, and weak effect from ACTH
Review: What are the major effects of aldosterone?
What cell types express MR?
increases transcription of Na/K pump, raises expression of EnACs, and Na/K/Cl cotransporter in the kidney, colon, salivary glands, and sweat glands
kidney, colon, salivary glands, sweat glands, liver, myocardium, and brain
Are there two types of MR?
Yes; low affinity receptor appears identical to GR (aldosterone binds only weakly to its low-affinity receptor)
How do cells prevent cortisol from acting on MR?
11beta-HSD2 activity produces inactive cortisone (NAD-dependent reaction)
Describe the renin-angiotensin-aldosterone system.
liver synthesizes and secretes angiotensinogen; renin, synthesized by granular cells in the JGA of the kidney cleaves angiotension in response to a decrease in effective circulating volume, cleaves angiotensinogen to angiotensin I (baroreceptor reflex); ACE, produced by pulmonary endothelial cells, cleaves angiotensin I to angiotensin II; on the plasma membrane of the glomerulosa, ang II binds to the AT1 receptor (Gq) and triggers synthesis of aldosterone via PLC; aldosterone exerts indirect negative feedback on RAAS by increasing effective circulating volume and lowering plasma potassium concentration (angiotensin II also negatively feeds back on renin release by acutely increasing blood pressure through vasoconstriction of vascular smooth muscle)
Does angiotensin II have a long half-life?
No; cleaved to angiotensin III by plasma aminopeptidases
How does extracellular potassium or ACTH induce aldosterone synthesis?
high extracellular potassium depolarized the plasma membrane and opens voltage-gated calcium channels (does not require PLC; synergistic to ang II); increases in ACTH raises intracellular cAMP and PKA stimulating calcium influx and aldosterone synthesis and endocytosis (ACTH also stimulates the fasciculata layer to produce glucocorticoids with some mineralocorticoid activity)
Is low aldosterone production life-threatening?
Describe why RAAS aggravates congestive heart failure.
reduced cardiac output in heart failure diminishes renal glomerular filtration (because of decreased blood pressure and enhanced sympathetic tone); kidney inappropriately assumes that extracellular volume is decreased and stimulates RAAS (results in edema and congestion in the systemic circulation)
What is a pathologic effect of aldosterone?
fibrosis in myocardium and blood vessel wall
Describe the blood supply of the renal medulla.
the medulla receives vascular input from vessels that begin in the subscapular plexus of the adrenal cortex; the vessels then branch into a capillary network in the cortex only to merge into small venous vessels that branch into a second capillary network with medulla
What is the significance of the adrenal medulla portal system?
medulla is exposed to the highest concentration of glucocorticoids and mineralocorticoids of all somatic tissue
Describe synthesis of catecholamines.
tyrosine hydroxylase converts tyrosine to d-dopa (rate-limiting step) in the cytosol of chromaffin cells and sympathetic nerve terminals; the cytosolic enzyme amino acid decarboxylase converts d-dopa to dopamine; a catecholamine/proton exchange (VMAT1) moves dopamine into membrane-enclosed dense-core vesicles (chromaffin granules); dopamine beta-hydoxylase converts dopamine to norepinephrine; NE may move from granules to cytosol where PMNT transfers a methyl group to produce epinephrine; secretory granules reuptake epinephrine through VMAT1
How is the proton gradient of the chromaffin granules maintained?
What are secretagogues for dopa and NE? E?
ACTH; cortisol upregulates PMNT
How are catecholamines stored? How are they released?
Are they bound in circulation?
bound to granular proteins, calcium, and ATP (chromogranins); not osmotically active; acetylcholine release from preganglionic neurons in the splanchnic nerves acts on nicotinic acetycholine receptors to depolarize the postganglionic chromaffin cell (secretion is accompanied by the release of ATP and granule proteins); in the circulation, catecholamines are free
How are catecholamines degraded?
by catecholamine-O-methyltransferase (COMT) present in endothelial cells, heart, liver, and kidney (converts to metanephrine); monoamine oxidase coverts metabolites to vanillymandelic acid; liver and gut conjugate these compounds to sulfate and glucuronide
How are adenocarcinomas different from benign adenomas in terms of production of hormones?
in adenocarcinoma, hormones normally produced by the gland and no longer produced
What tissues have the highest representation of beta 1 receptors?
cardiac myocytes and JGA cells of the kidney
What is a nongenomic effects of thyroid hormone?
modulates oxidative phosphorylation through adenine nucleotide translocase (exchanges matrix ATP for cytosolic ADP)
What is the downstream signaling pathway of receptor tyrosine kinases?
How is receptor-mediated signaling terminated?
internalization of receptor followed by degradation or recycling in the lysosomes; inactivation of signaling protein or production of inhibitory protein
Describe radioimmune assays.
The more hormone in a patient's blood sample the lower the radioisotope activity (competition between radiolabeled hormone and endogenous hormone) through analyzing Scatchard plot
What is a major theme in regards to the expression of hormones and their target receptors? Give an example.
Most physiological responses to a particular hormone are maximally activated when only a fraction of the total number of receptors are occupied by the hormone
physiological response to insulin is achieved from binding only 10% of insulin receptors
What is the difference between potency and efficacy?
potency refers to the dose required to achieve a maximal response (if an agonist must be prescribed at a higher dose than an endogenous compound, it has decreased sensitivity)
efficacy is the drug's capacity to produce an effect (agonists may either have increase or decreased responsiveness)
Is the adrenal medulla essential for life?
No; Medullary insufficiency can be alleviated by norepinephrine released by sympathetic system
Is POMC-processing the same in various corticotrophs?
No; products can be alpha-MSH, beta-MSH, ACTH, B-LPH, and J peptide
What are the effects of increased secretion from the adrenal medulla?
increases contractility of the heart, increased blood pressure and heart rate; increased blood flow to skeletal muscles and liver; increased ventilation/bronchial smooth muscle relaxation
Increased lipolysis (adipocytes) and glycogenolysis (muscle/liver)
How can testosterone be produced pathologically in women?
synthesis in the reticularis layer of the adrenal cortex
Is conversion of cortisol to cortisone NAD-dependent? What cell types are able to convert cortisol to cortisone?
No; NADP (hepatocytes, adipocytes, and neutrophils)
How is cortisol (cortisone) measured in the clinical setting?
multiple blood withdrawals throughout the day (one single measurement is not enough)
Is aldosterone free in the circulation?
partially bound to circulating proteins
Androgen and estrogen synthesis occurs in what parts of the adrenal cortex?
only reticularis layer
How is cortisone converted to cortisol in the liver?
coupled to pentose phosphate pathway (G6P enters the endoplasmic reticulum and is converted by H6PD to 6-P-gluconate generating NADPH from NADP; NADPH is used by the 11-b-HSD1 to generate active cortisol from inactive cortisone)
Which hormones antagonizes angiotensin II in the zona glomerula and inhibits renin secretion? Where is it produced?
atrial natriuretic peptide; atrial myocytes
What is the major source of local, non-ovarian estradiol in post-menopausal women?
Describe the difference in the granular composition of epinephrine-secreting and norepinephrine-secreting cells.
Epinephrine-secreting cells are stored in larger and less dense granules (primary type of granule in medulla)
Which catecholamine is the primary component of sympathetic tone under normal physiologic conditions?
What is the only catecholamine synthesized in chromaffin granules?
norepinephrine (from dopamine by dopamine beta-hydroxylase)
What are the two mechanisms for release of catecholamines?
kiss and run and full fusion
What is the function of sympathetic tone under basal conditions? with stress?
maintains blood pressure, heart rate, vascular tone, enteric activity, and blood glucose level
there is maximal catecholamine release resulting in increased blood pressure, cardiac output, pulmonary ventilation, increased blood flow to muscle, and glucagon secretion
Describe the mechanism behind stimulation of chromaffin cell catecholamine endocytosis. What changes with persistent splanchnic firing?
Catecholamine release from chromaffin cells is under the control of acetylcholine (increased intracellular calcium)
Nicotinic pathway rapidly desensitizes under persistent splanchnic firing; Catecholamine secretion persists via the action of a non-cholinergic peptide transmitter (PACAP from VIP-glucagon superfamily; Gs g protein mechanism; increased production of Epac and activation of PKC) released from splanchnic nerve
Epinephrine acts primarily on what adrenergic receptors? NE?
beta (1 and 2; Gs); alpha 2 (Gi; and sometime alpha 1, Gq)