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Flashcards in Renal Deck (163):

What is the uriniferous tubule - function, components, and where they are located

Uriniferous tubule - microscopic, functional unit of the kidney responsible for blood filtration and urine formation; ultrafiltrate --> forming urine (reabsorption and secretion)
renal corpuscle= glomerulus + Bowman's capsule- in renal cortex,
proximal convoluted tubule - in renal cortex,
loop of henle - both cortex and medulla,
distal convoluted tubule - in renal cortex,
collecting duct- both cortex and medulla


What is the difference between nephron and uriniferous tubule?

Nephron - Renal corpuscle (glomerulus + Bowman's capsule), PCT, loop of henle, and DCT
uriniferous tubule - nephron + collecting duct


Describe the histological components of the kidney

Cortex - has medullary rays (collecting ducts) and cortical labryinth (renal corpuscles)
Medulla - homogenous - only straight bits


What is the glomerulus? What are the components and functions of the glomerular filtration barrier?

1) Glomerulus - modified capillaries of the renal corpuscle
2) Glomerular filtration barrier - goal to keep protein out of the forming urine;
Fenestrated endothelium (retains negative charge), shared basement membrane- lamina rara externa, lamina densa, lamina rara interna (filters large and (-) proteins), foot processes of podocyte ie pedicels (slit diaphragm tight junction between pedicels for materials to cross through)


Describe the arterial and venous components of the kidney

renal artery --> segmental --> interlobar --> arcuate --> interlobular --> afferent arterioles of glomerulus --> glomerulus --> efferent arterioles --> vasa recta --> renal veins --> systemic circulation


kidney lobe
renal papilla
vascular pole
urinary pole
area cribosa

1) kidney lobe = medullary pyramid (8-18 in kidney)
2) renal papilla - tip of medullary pyramid, where urine exits into excretory passages (minor calyx --> major calyx --> ureter)
3) lobule- nephrons grouped around single medullary ray and draining into single collecting duct
4) vascular pole - where afferent and efferent arterioles enter and exit from glomerulus
5) urinary pole- where ultrafiltrate leaves
6) area cribosa - holes in the papilla, where collecting ducts terminate


Where does efferent arteriole of glomerulus go?

forms capillary beds around the tubule, returns materials reabsorbed from the forming urine into the blood circulation
2 divisions of peritubular capillaries:
1) cortex - peritubular plexus
2) medulla (loop of Henle) - vasa recta


What are the three types of cells of the glomerulus?

1) mesangial - structural core of glomerulus, secrete matrix, remove debris from filtration apparatus, regulate blood flow

2) endothelial- part of glomerular filtration barrier

3) podocytes- part of glomerular filtration barrier


What is the pathology of the glomerular basement membrane in diabetics?

abnormally thick basement membrane is less effective barrier and allows proteins to get into the urine --> proteinuria


Describe the pathology of nephrin mutation in podocytes

Nephrin - in slit diaphragm that connects adjacent pedicels from different podocytes;
With nephrin mutation - pedicels not as tightly adhered to the basement membrane as they should be --> allow proteins into the urine --> proteinuria


Describe the epithelium of:
1) Bowman's capsule
2) PCT
3) Loop of Henle
4) DCT
5) Collecting duct
6) Calyces and renal pelvis

1) Bowman's capsule - simple squamous

2) PCT - simple cuboidal + brush border consisting of microvilli (transition is at urinary pole which is start of PCT

3) Loop of Henle - thick ascending/descending are cuboidal, thin ascending/descending are simple squamous

3) DCT- simple cuboidal without brush border

4) Collecting duct - cuboidal without brush border

5) Calyces and renal pelvis - transitional epithelium


Describe the histology of the:
1) PCT
2) Loop of Henle
3) DCT
4) Collecting duct
5) Calyces and renal pelvis
6) Ureter
7) Urethra

1) PCT - simple cuboidal with brush border that looks like ragged lumen, central nuclei, indistinct cell borders, eosinophilic (lot of mitochondria to fuel transporters), membrane infoldings for extra space to dump absorbed materials which appear as striated line

2) Loop of Henle - region of macula densa where loop passes close by to the corpuscle that spawned it

3) DCT - distinct luminal margin ie no brush border, apical nuclei, less eosinophilic but still striated

4) Collecting duct- 2 cell types, principal for water balance and intercalated for acid/base regulation, distinct cell borders, domed apex juts into lumen

5) Calyces and renal pelvis- uppermost nuclei round, binucleated cells

6) Ureter- star shaped lumen, outer circular and inner longitudinal muscle layers

7) Urethra- U-shaped lumen, outer circular and inner longitudinal muscle layers


How do you distinguish PCT from DCT?

1) LM: PAS staining - PC stains positive (dark) and DCT stains negative (light)
2) EM: PCT has brush border (consisting of microvilli) while DCT does not


What is the juxtaglomerular apparatus? Describe tubuloglomerular feedback?

1) Function: regulates filtration rate at the glomerulus, regulates blood pressure
Components: macula densa (end of TAL/start of DCT that passes near glomerulus), JG cells of the afferent arterioles, extraglomerular mesangial cells (middlemen between MD and JG)

2) Tubuloglomerular feedback - higher blood flow --> higher GFR --> high NaCl in macula densa, which is sensed through the apical NKCC2 transporter --> macula densa feeds back on glomerulus to decrease renin release, signals afferent arteriole to vasoconstrict --> decreases blood flow and GFR

(eg if NaCl is low, macula densa signals afferent arteriole to dilate --> increased RBF and GFR + increased renin release by JG cells)


What are juxtaglomerular cells (JG cells)?

JG cells - modified smooth muscle cells, mainly in the walls of the afferent arterioles
regulate GFR minute by minute by constriction and dilation of afferent arterioles in a given glomerulus (autocratic)
also globally regulates blood pressure and GFR on longer time scale through renin secretion (democratic)

*Meanwhile, AT1Rs are mostly found in efferent arterioles, AII binds to vasoconstrict to increase GFR*


What is the relative distribution of body water? What is third spacing?

1) Intracellular fluid - 67%
2) Extracellular fluid - 33%
--> blood volume (1st space)- 8%
--> interstitial fluid (2nd space)- 25%
*decrease in ECF triggers SNS and RAAS system*
3) Third spacing - pathological condition where fluid is where it should not be eg edema


1) effective solute
2) effective osmolality
3) effective circulating volume ECV (how is this measured)
4) renal clearance C

1) effective solute- solutes which cannot passively diffuse across cell membrane eg Na+, glucose --> sets tonicity to create osmotic gradient

2) effective osmolality - concentration of effective solutes in given weight of H20; = 2[serum Na+] + glucose/18, should be ~290

3) effective circulating volume ECV - blood volume required for adequate perfusion of vital organs *changes moment to moment depending on metabolic factors --> measured as the pressure perfusing arterial baroreceptors in carotid sinus or afferent arterioles

4) Renal clearance C- volume of blood that is completely cleared of solute into urine per unit time (mL/min)


Define glomerular filtration rate GFR
What is the threshold GFR?
When does GFR = clearance?

1) GFR- rate at which solutes are filtered from glomerulus into Bowman's capsule collecting reservoir; GFR = [[urine] * urine flow (ml/min)] / [plasma]

2) GFR less than 60 - associated with high risk for devlpt of cardiovascular disease

3) GFR = C when solute is freely filtered, neither reabsorbed nor secreted eg inulin


1) What is the relationship between GFR and serum creatinine and BUN (blood urea nitrogen) measured in blood?
2) What is the normal range for creatinine, BUN, GFR, and BUN:Cr?
3) How do the following factors affect serum creatinine?
-hispanic + asian
-kidney disease
-large muscle mass
-eating red meat
4) What factors will increase serum BUN?

1) Increased GFR --> decreased in serum creatinine and BUN and vice versa
2) Pcr less than 1.5 mg/dl; BUN 10-20 mg/dl; GFR 75-125; BUN:Cr 10:1 ratio
3) Black-increase;
kidney disease- decrease;
high muscle mass- increase;
eating red meat - increase;
malnutrition - decrease
4) High protein, volume depletion/dehydration (and thus hypoperfusion) --> manifests as high BUN without increase in creatinine (BUN:Cr > 20:1)


filtered load
fractional excretion
filtration fraction

1) filtered load - amount of solute x filtered into bowman's capsule per unit time
2) fractional excretion - ratio of solute excreted : filtered load (% of solute filtered that actually ends up in excreted urine) = [X]excreted / (GFR * [X]plasma)
3) filtration fraction - fraction of renal plasma flow that is filtered across the glomerular capillaries = GFR/RPF


Describe the tubulo-glomerular feedback (TGF) system when there is increased GFR.

What happens during increased volume expansion (pathologic situation)?

1) Increased GFR --> increased NaCl in urine --> depolarize and activate macula densa cells *(in TAL, close to juxtaglomerular apparatus embedded around afferent arteriole)*--> secrete vasoconstrictors to afferent arterioles --> decreases glomerular pressure --> reduces GFR

2) Increased volume expansion --> increased ECF --> increased GFR --> increased excretion of H20+ Na+ (pressure natriuresis) --> macula densa lumenal Na+ relatively low compared to H20 --> desensitizes TGF --> higher glomerular P and increased GFR --> in order to restore euvolemia, need lots of urine excretion (diuresis)
*Note: ANP decreases sensitivity of TGF mechanism to increase diuresis*


Describe how the RAAS system responds to hypovolemia (how is it turned on and off)

1) low volume --> low blood pressure sensed by baroreceptors (carotid sinus, afferent arterioles)--> activates SNS tone --> activates beta 1 adrenoreceptors on JG cells --> secrete renin --> renin converts angiotensinogen to AI --> ACE converts AI to AII --> AII binds to AT1 receptor on efferent arteriolar vascular smooth muscle --> vasoconstricts efferent arteriole --> increases glomerular pressure (through back pressure) into optimal range --> increased GFR --> increased reabsorption of Na+ from filtrate into renal interstitium and back into circulation (this is also facilitated by lowered capillary pressure due to reduced renal perfusion and lower renal blood flow RBF from AII binding to AT1R)--> increases volume

2) once sufficient volume/MAP/perfusion pressure is reached --> SNS tone downregulated --> Decreased renin secretion --> RAAS turned off


Describe the mechanism of ARBs

ARBs selectively block AT1 receptors:
1) Directly blocks vasoconstriction (reduces glomerular pressure GFR)
2) Directly inhibits Na+ reabsorption (NHE3, NKCC2, NCC, EnaC)
3) Inhibition of aldosterone production and secretion from adrenal cortex
4) Possibly promotes release of bradykinin via AT2R --> vasodilation and natriuresis


Describe the phenomenon of ACE escape and how it explains the limited effectiveness of ARBs and ACE inhibitors in some patients

AII production impaired --> feedback inhibition of renin is lost --> reactive increase in renin --> AII produced through ACE independent pathways
*option is to use combination of renin inhibitors and ARBs


What is the effect of SNS activation?

Postganglionic SNS fibers secrete norepi --> activates alpha1 adrenoreceptors in vascular smooth muscle --> systemic vasoconstriction --> reduction in GFR and renal perfusion --> volume conservation;
Norepi also activates beta1 adrenoreceptors on JG cells to secrete renin


Describe the activation and function of AVP

1) Activation - hyperosmolality detected by osmoreceptors, hypotension detected by baroreceptors (carotid sinus and afferent arterioles) --> induces posterior pituitary to secrete AVP

2) Function: Peptide that binds to V1R receptor in arterioles --> vasoconstriction;
Binds to V2R receptor in nephron --> activates aquaporins --> stimulates H20 + Na reabsorption --> increased volume


Describe the activation and function of ANP

ANP=natriuretic peptide
1) Activation - secreted by atrial myocytes when right atrium is distended (increased right atrial pressure due to increased volume)

2) Function - vasodilation within arterioles, decreases sensitivity to TGF, increases GFR and RBF (Renal blood flow), suppresses renin secretion, increases diuresis


What is the importance of renal perfusion?
Describe the process of autoregulation during low BP?

1) Renal perfusion - maintain adequate 02 delivery, maintain optimal hydrostatic and oncotic pressures for reabsorption

2) Low BP --> sensed by afferent arteriole pressure sensor --> activates vasodilatory prostaglandins (afferent arterioles) + RAS (vasoconstricts efferent arteriole which contain AT1 receptors for AII) --> increased glomerular pressure --> increased GFR + RBF


What happens if BP is too low (outside of range of autoregulation)?
What are some causes of renal hypoperfusion (lack of blood flow to kidney)?
What are the symptoms of renal hypoperfusion?

1) BP too low (pathophysiologic) --> locally produced vasoconstrictors --> act on afferent arterioles --> lower glomerular pressure + GFR --> reabsorptive gradients impaired --> ischemic acute renal failure

2) Causes: anything that impedes blood delivery to the nephron eg impaired CO, renal artery stenosis, volume depletion, prerenal azotemia (increase in BUN)

3) Symptoms: Increased urinary specific gravity, decreased urinary Na+ and urea, BUN:creatinine > 20:1


Describe the ion+glucose reabsorption in:
the proximal tubule (PCT)

majority of Na+ reabsorbed in first half of PCT;
basolateral (bw epithelium and interstitium): Na/K+ ATPase sets favorable gradient, transport also through Na+/HC03- symporter;
transport across apical (bw lumen and epithelium): SGLT1/2 glucose/Na+ transporters, and Na+/H+ exchanger NHE3
*passive Ca2+ reabsorption in PCT*


Describe the ion+glucose reabsorption in:
Loop of Henle
thick ascending limb (TAL)

1) Na+ reabsorption from thin ascending limb through Na+ pumps
2) diluting segment - impermeable to H20 reabsorption;
basolateral: Na/K ATPase and CL/HC03 exchanger;
apical: ROMK2 secretes K+, facilitates NKCC2 (reabsorbs K, CL, Na), Na/H exchanger NHE3


Describe the ion+glucose reabsorption in:
distal convoluted tubule (DCT)

basolateral: Na/K ATPase, transporters that reabsorb Cl-, K+ into interstitium, Na+ (into cytoplasm)/Ca2+ (out) exchanger;
apical: Na/Cl cotransporter NCC, Na+ transporter ENaC, + another transporter that reabsorbs Ca2+


Describe the ion+glucose reabsorption in:
cortical collecting tubule (CCT)

aldosterone-sensitive distal nephron
basolateral: Na/K ATPase (stimulated by AVP, AII, aldosterone);
apical: K+ secretion by ROMK2 creates positive charge gradient for Na+ reabsorption through ENaC (stimulated by AVP, AII, aldosterone), H+ secretion and bicarb formation through ATPase (stimulated by aldosterone)


Describe the mechanism of the following diuretics, where they act, and whether they are K+ sparing or wasting:
1) Acetazolamide
2) Furosemide
4) Amiloride
5) Spironolactone/Eplerenone

1) Acetazolamide - (PCT, weak)- carbonic anhydrase inhibitor, blocks H+ formation and bicarb reabsorption

2) Furosemide loop diuretic- (Loop of Henle, powerful) -blocks NKCC2 transporter --> blocks Na, Cl, K reabsorption --> K+ wasting --> charge gradient leads to Ca2+ wasting

3) HCTZ thiazide diuretic - (DCT, weak) - blocks NCC tranporter --> blocks Na+ and Cl- reabsorption --> charge gradient leads to K+ wasting and Ca2+ sparing

4) Amiloride - (CCT) - blocks ENaC Na+ transporter --> K+ sparing

5) Spironolactone/eplerenone (CCT) - aldosterone antagonist --> K+ sparing, used to treat resistant hypertension


1) where is it secreted
2) what stimulates secretion
3) where does it bind
4) Function

1) Zona glomerulosa of adrenal cortex
2) Elevated AII and hyperkalemia (K+ depolarizes outer membrane and activates voltage gated Ca2+ channels to stimulate aldosterone synthesis)
3) mineralocorticoid type steroid receptor in principal cells and VSM
4) combats volume depletion: (acute) stimulates Na+ reabsorption through ENaC --> H20 reabsorption (chronic) stimulates Na/K ATPase, K+ excretion through ROMK2


Describe the aldosterone paradox

1) Hyperkalemia - only increases aldosterone (not AII expression) --> gene changes cause aldosterone to be more attracted to ROMK than ENaC --> promotes K+ excretion without excess Na+ reabsorption/hypervolemia
2) Hypovolemia - RAAS activated --> AII and aldosterone cause Na+ reabsorption --> H20 reabsorption and volume rebalance without hypokalemia


Describe aldosterone escape

Pressure natriuresis - Na+ and H20 excretion even with high levels of aldosterone, bc MAP and blood pressure are too high;
K+ excretion high in distal nephron when aldosterone levels are high;
*thus patients with hyperaldosteronism are more likely to be hypokalemic than hypernatremic (bc there is this mechanism of pressure natriuresis which overrides aldosterone if BP is too high)*; on the flip side, hypoaldosteronism leads to hyponatremia (not bc there is less Na+ reabsorption/more excretion, but because the low volume/BP activates AVP --> more H20 reabsorption compared to [Na+])


Explain the different effects of increased Na+ on renal RAAS vs brain RAAS.
Explain how the brain is potentially involved in the pathophysiology of hypertensive disease through the cardiotonic steriod ouabain.

1) Renal RAAS: increased plasma Na+ --> increased Na+ and H20 retention --> increases plasma volume --> increases blood pressure --> once BP/perfusion pressure/MAP is achieved, SNS downregulated --> renal RAAS turned OFF

2) Brain RAAS for salt-sensitive populations: increased plasma Na+ --> increased NaCl in CSF --> brain RAAS turns ON --> production of ouabain --> vasoconstriction --> decreased pressure natriuresis --> vicious cycle of chronic HTN *direct association with dietary NaCl and induction of hypertension in salt-sensitive population*


What factors stimulate the reabsorption from interstitium into capillaries (and thus the blood plasma/ECV)?

Filtration = Pcap - Pif + PIif - PIcap
Reduced flow in capillaries reduces Pcap, while the Pif is high bc it is related to the pressure of forming urine
Glomerular filtration increases PIcap, while PIif is low
Overall, filtration # is low --> favors reabsorption


Describe the condition, causes, and presentation for:
1) Euvolemic hyponatremia
2) Hypovolemic hyponatremia
3) Hypervolemic hyponatremia

1) Euvolemic hyponatremia - inordinate water retention + normal Na+ content;
cause: SIADH;
presentation: otherwise healthy patient

2) Hypovolemic hyponatremia - both H20 and Na+ loss, but more Na+ lost proportionally;
cause: (intrarenal) diuretics, aldosterone deficiency, (extrarenal) intravascular fluid loss through diarrhea, vomiting, sweating, hemorrhage;
presentation: (intrarenal) increased urine Na+ (extrarenal) decreased urine Na+, increased BUN due to hypoperfusion, tachycardia, flattened neck veins

3) Hypervolemic hyponatremia = dilutional hyponatremia due to H20 retention
cause: heart failure, renal failure, drinking lots of water while exercising
presentation: heart failure- decreased urine Na+ (conserve H20 to raise volume and perfusion pressure), renal failure - increased urine Na+ (renal function and thus Na+ reabsorption impaired)


Describe the condition, cause, and presentation for:
1) Mineralocorticoid hypertension
2) Pseudohypoaldosteronism

1) Mineralocorticoid hypertension - aldosterone excess hyperstimulates ENaC;
cause: primary (Conn's disease e.g. tumor, would have high PAC:PRA) or secondary (e.g. renal artery stenosis) hyperaldosteronism;
presentation: hypertension bc increased aldosterone --> increased Na+ reabsorption --> increased blood volume --> increased venous return --> increased CO --> increased BP (=COxTPR), hypokalemia (aldosterone promotes K+ excretion through ROMK)

2) Pseudohypoaldosteronism - disruption in ENaC leading to Na+ excretion (natriuresis) and K+ accumulation;
cause: mutation in SCNN1 gene for ENac;
presentation: hypotension (increased PRA), hyperkalemia, metabolic acidosis, can have high plasma aldosterone


Describe the causes (neurogenic and nephrogenic) and presentation for:
1) Diabetes insipidus

1) Diabetes insipidus - loss in AVP production (neurogenic) or AVP resistance bc of V2R or AQP2 mutation- (nephrogenic);
presentation: polyuria- large volumes of dilute urine (*dilute aspect differentiates this from DM, where there is glucose in urine)--> hypovolemia, polydispia (reduced plasma volume and hyperosmolality triggers osmoreceptors to activate hypothalamic thirst centers), hypotension (reduced ECV), hyper/hyponatremia (ion imbalance due to immense water excretion);
treatment - (central) AVP analog, (nephrogenic) thiazide diuretic

2) SIADH - increased AVP production (neurogenic) or increased AVP response eg gain of function mutation in V2R (nephrogenic);
presentation: euvolemic hyponatremia (although AVP causes both Na+ and H20 reabsorption, more water is reabsorbed leading to a low Na+ concentration); presents normally, NO hypertension (bc the increased fluid is ICF, not ECF, so does not affect blood volume/pressure); blood labs show concentrated urine (high specific gravity), increased urine [Na+], hypoosmolality


How do the following mechanisms regulate NaCl transport:
1) Glomerular-Tubule balance
3) SNS-norepi
4) ANP, prostaglandins, bradykinin, dopamine

1) GT balance - PCT can absorb constant fraction of filtered load --> as more Na+ is filtered, more is reabsorbed

2) RAAS - Na+ reabsorption through upregulation of NHE3 in PCT, ENaC in DCT, aldosterone secretion

3) SNS - Na+ reabsorption by stimulating RAAS via beta1 adrenoreceptors on JG cells, activating NHE3 and Na/K
ATPases via alpha adrenoreceptors ; reduces GFR and RBF

4) ANP, prostaglandins, bradykinin, dopamine- all impair Na+ reabsorption and decrease plasma [Na+]


Explain how H+ is secreted through:
1) lumenal buffers
2) protein metabolism
3) NH3-NH4+ buffer system

*both occur in PCT
1) H20 dissociates into OH- and H+ in the peritubular epithelial cytoplasm --> H+ is excreted as H2P04 and OH- combines with C02 to make HC03-

2) Glutamine is metabolized in epithelial cytoplasm into NH4+ (excreted) and alphaketoglutarate (used to make bicarb)

3) In PCT, NH3 + H+--> NH4+ which travels with forming urine to TAL where it is reabsorbed into epithelium and then dissociates;
NH3 diffuses into interstitium --> recycled in PCT to make more NH4+ (thereby buffering low pH) OR secreted as NH4+ from collecting tubule in distal acidification (thereby reducing acid load) --> end result is removing H+ from circulation


Explain the relationship between kalemic and acid/base status

in order to maintain electroneutrality:
Hyperkalemia ---> Metabolic acidosis, and
hypokalemia --> Metabolic alkalosis
low K+ --> gradient for K+ to move from intracellular to extracellular interstitium--> H+ moves from extracellular to intracellular --> intracellular acidosis --> H+ secretion/HCO3- reabsorption --> metabolic alkalosis


When do you calculate urine AG? Why is it negative if the kidneys are healthy?

1) Calculate with normal AG metabolic acidosis; UAG = Na+ + K+ - Cl-

2) When pH is low, healthy kidneys reduce acid load by secreting NH4+ in the form of NH4Cl --> urine has high [Cl-]
--> UAG negative;
When kidneys are not healthy, cannot acidify the urine --> lower [Cl-] in urine --> UAG positive


1) How does hyperaldosteronism lead to hypokalemic metabolic alkalosis?

2) How does hypoaldosteronism lead to hyperkalemic metabolic acidosis? *common cause is congenital adrenal hyperplasia*

1) Hyperaldosteronism --> increased activity of H+/K+ and H+ ATPases --> increased H+ secretion in collecting duct --> increased HC03- reabsorption --> increased pH --> decreased extracellular H+ --> gradient for H+ to come out of cells, K+ to go into cells --> hypokalemic metabolic alkalosis

2) Hypoaldosteronism --> decreased aldosterone --> decreased H+ secretion --> decreased HC03- generation --> decreased pH --> H+ goes into cells, K+ comes out of cells --> increased extracellular K+ --> hyperkalemic metabolic acidosis


What is the renal response to alkalinity?

Kidneys do NOT upregulate HCO3- excretion (by reducing bicarb resorption *bicarb is not secreted, only filtered and reabsorbed*. Instead they downregulate NH4+ excretion (which is combined with HC03- reabsorption when glutamate is broken down in the process of protein metabolism) --> decreases HC03- reabsorbed --> lowers blood pH


Explain how urea recycling promotes H20 absorption

PCT - 50% filtered load reabsorbed
Loop of Henle - 110% filtered bc lot is secreted
Collecting duct - urea reabsorbed into interstitium, final excreted is 20% of filtered load
high concentration of urea in medullary interstitium creates favorable oncotic gradient for H20 reabsorption esp when AVP is activated and aquaporins open up


What are cells in the endocrine pancreas are responsible for secreting?

Islets of Langerhans = endocrine pancreas
alpha cells - glucagon (increases plasma glucose through glycogenolysis and gluconeogenesis, acts in the liver)
beta cells - insulin (decreases plasma glucose)
delta cells - somatostatin (inhibits GH to decrease plasma glucose)


1) glycogenesis
2) glycogenolysis
3) gluconeogenesis
4) lipogenesis

1) glycogenesis - glucose uptake and storage as glycogen
2) glycogenolysis - metabolism of glycogen into plasma glucose
3) gluconeogenesis - synthesis of glucose from other substrates
4) lipogenesis - formation of FFA and uptake of FFA into cells


When is insulin synthesized?

What is the result of a decrease in insulin?

1) Synthesized when plasma glucose > 100 mg/dl (max insulin release at 300), circulates in bioactive form and binds to receptors that mediate rapid influx of glucose by facilitated diffusion

2) Normally, insulin leads to lipogenesis. With low insulin, glycolysis shifts to lipolysis --> FA oxidation --> ketone bodies --> oxidative fuel
* if ketoacid production > usage --> can lead to diabetic AG ketoacidosis*


What is the function of insulin in:
1) skeletal muscle
2) fat
3) the liver
4) protein
5) bone

*insulin at low levels is v good at cellular K+ uptake i.e. reducing plasma K+ levels*

1) Skeletal muscle: promotes glucose uptake and glycogenesis *major site of post-prandial glucose uptake* (opposite action of GH and cortisol, which suppress glucose uptake by muscle)

2) Fat: stimulates lipogenesis (FFA uptake for combination with glucose to produce triglycerides), blocks lipolysis (opposite action of GH, which promotes lipolysis to produce FFA for skeletal muscle fuel)

3) Liver: promotes glucose uptake and glycogenesis, inhibits gluconeogenesis and glycogenolysis, stimulates fatty acid synthesis (opposite action of GH, which stimulates gluconeogenesis)

4) Protein: impairs protein catabolism --> anabolic (in conjunction with GH)

5) Bone: anabolism (in conjunction with GH)


What are the 3 P's of DM (DMI and diabetes insipidus) and what are their pathologies?

1) Polydispia - increased glucose --> hyperosmolality --> activates thirst centers in the hypothalamus (increased levels of AII trigger thirst)
2) Polyuria - more glucose in forming urine --> draws Na+ and H20 out (mainly in PCT) --> osmotic diuresis --> decreases ECF volume --> decreased blood pressure, triggers SNS and RAAS; *DI polyuria is due to lack of AVP --> more dilute urine excreted*
3) Polyphagia - loss of insulin which is an anabolic hormone leads to weight loss and increased appetite


What are treatment options for DMII?

1) Weight loss and exercise
2) metformin - inhibits liver gluconeogenesis, enhances insulin receptor signaling
3) thiazolidenediones - insulin sensitizer
4) sulfonylurea - promotes endogenous insulin production in pancreatic beta cells
5) insulin replacement - injectables, pump


Describe the regulation of Ca2+ and P04 during

Hypocalcemia --> chief cells of the parathyroid glands secrete PTH:
1) resorption of bone --> increased plasma Ca2+ and P04
2) renal Ca2+ reabsorption (distal nephron i.e. TAL, DCT, collecting tubules)
3) impairs renal P04 reabsorption (proximal tubule)
4) stimulates Vitamin D/calcitriol synthesis --> Ca2+ reabsorption (distal nephron) + small intestine
*Vit D also promotes renal P04 reabsorption, but PTH wins out so end result is increased phosphaturia*; Vit D feeds back and inhibits PTH secretion


Describe the countercurrent exchange mechanism in the vasa recta

Vasa recta - loops of capillaries with low blood flow that run parallel to loop of henle;
Maintain hypertonicity of the medullary interstitial osmotic gradient by recycling NaCl, H20, urea from medullary interstitium --> systemic circulation;
nephron (loop of Henle)- countercurrent multiplier - sets up osmotic gradient for diffusion


What is one watchout for providing insulin therapy to diabetics (eg for diabetic ketoacidosis)?

Hypokalemia - need to monitor K+ status when giving insulin;
Although metabolic acidosis (e.g. ketoacidosis) is associated with hyperkalemia, in diabetics: increased glucose --> hyperosmolality --> osmotic diuresis --> increased aldosterone --> loss of total body K+ (through ROMK);

Insulin leads to further cellular K+ uptake (decreased plasma K+) --> so when administering insulin therapy, watch out for hypokalemia


What is the function of glands and their general histology?

Glands - synthesize, modify, and secrete products;
cuboidal or columnar epithelial cells surrounded by basement membrane


1) Exocrine glands
2) Endocrine glands
2A) endocrine action
2B) autocrine action
2C) paracrine action

1) Exocrine- maintain contact with tissue surface; secrete products into ducts eg salivary, sweat, mammary glands

2) Endocrine - lose contact with tissue surface, secrete into blood stream via fenestrated capillaries
A) endocrine action - tissues are far removed from site of secretion
B) autocrine action - secretions activate secreted cell itself
C) paracrine action - secretions activate adjacent cells


What are four types of products produced by endocrine glands? Give examples

1) modified AA eg adrenaline from adrenal medulla

2) Peptide hormones eg AVP from posterior pituitary (produced in hypothalamus)

3) Glycoprotein hormones eg FSH, LH, TSH, GH- all from anterior pituitary

4) Steroid hormones eg aldosterone from adrenal cortex


1) Many peptide hormones require post-translational modifications to produce active hormone
2) All hormones bind to cell surface receptors to activate second messenger systems
3) Hormone activity is regulated by negative feedback loops

1) True

2) False- protein/peptide hormones do this bc they are hydrophilic, but steroid hormones are hydrophobic and can diffuse through plasma membrane and into nucleus to bind to nuclear receptors and directly regulate gene transcription

3) True


Describe the histologically/functionally distinct lobes of the pituitary gland (ie hypophysis) and their embryology

1) Adenohypophysis= Pars distalis (Anterior lobe) + Pars intermediate + Pars tuberalis -- glandular tissue, from oropharynx ectoderm (called Rathke's pouch)

2) Neurohypophysis = Pars nervosa (Posterior lobe) + infundibulum -- axon terminals and pituicytes, from neuroectoderm/neural secretory tissue


Describe the hypophyseal portal system that links the hypothalamus and the pituitary

Hypothalamic peptides that regularly pituitary secretion collect at fenestrated primary capillary plexus (located at median eminence of hypothalamus) -- formed by superior hypophyseal artery --> portal veins --> secondary plexus at anterior pituitary which bathes cells of the anterior lobe;
inferior hypophyseal artery supplies posterior lobe


Describe the three histologically distinct cell types that can be observed in the anterior pituitary

1) Acidophilic - stain light pink, contain somatotrope GH, lactotrope PRL prolactin (non-glycosylated)

2) Basophilic - stain dark pink, contain thyrotrope TSH, corticotrope ACTH, gonadotrope FSH, LH (glycosylated)

3) Chromophobe - don't stain bc don't have secretory granules


Describe the 3 main cell types in the posterior pituitary

1) Herring bodies - axon terminals containing stored hormone -- oxytocin (cell bodies in paraventricular nuclei) and ADH/AVP (cell bodies in supraoptic nuclei of hypothalamus) -- precursors bound to neurophysins during transport, mature peptides released through fenestrated capillaries; large and light staining

2) Pituicytes - glial cells that support Herring bodies; small and dark staining
3) Endothelial cells - comprise fenestrated blood vessels of the gland


Describe the embryology and histology of the thyroid gland.

How can the activity of individual thyroid follicles be observed histologically?

1) Derived from endoderm; tubules containing parafollicular C-cells that produce calcitonin derived from 5th pharyngeal pouch

2) Follicle = single layer of cuboidal epithelium composed of follicular cells surrounding extracellular accumulation of secreted colloid (thyroglobulin + iodine); capillaries and lighter staining C cells also present

3) Thyroid follicles actively taking up colloid to produce thyroid hormone are cuboidal, whereas cells with flattened epithelium have less colloid uptake


Describe the synthesis and secretion of thyroid hormone in follicular cells.

Where does the majority of biologically active thyroid hormone come from?

I. Synthesis
1) Follicular cells take up iodide through I-/Na+ symporter
2) Oxidation: Inorganic iodide + TPO enzyme + H202 --> active iodine
3) Iodination: Active iodine + thyroglobulin + TPO enzyme--> MIT or DIT (depending on how many iodine added)
4) Coupling: DIT + DIT + TPO--> T4 (weakly active); MIT + DIT +TPO --> T3 (V active) or reverse rT3 (not active)
5) stored in lumen of follicle as colloid

II. Release
1) TSH binds to basal membrane
2) Colloid endocytosed and fused with lysosome
3) Colloid degraded - T3 (7%), rT3 (2%), and T4 (91%) released through basal membrane into bloodstream
4) In peripheral tissue (liver + kidneys): T4 + 5' deiodinase enzyme --> T3
*majority of circulating T3 derived from T4*


1) Describe the regulation of thyroid hormone secretion through the hypothalamic-pituitary-thyroid axis.

2) What is the result of TSH stimulation of follicular cells in the thyroid gland? What is the associated clinical abnormality?

1) Environmental stress (ie increased caloric intake, cold temp, lectin) --> TRH produced in hypothalamus --> goes to anterior pituitary via hypophyseal portal system --> basophilic thyrotrophs secrete TSH --> TSH binds to receptors on surface of follicular cells --> Activate thyroid hormone biosynthesis through cAMP; T3 and T4 negatively feedback on TRH and TSH

A) activation of thyroglobulin and TPO expression
B) activation of Na/K ATPase (leading to increased I- uptake through the Na/I symporter)
C) enhancement of rate of oxidation/iodination/coupling
D) colloid endocytosis
E) stimulation of fusion of colloid with lysosomes
F) increases size (hypertrophy) and number (hyperplasia) of follicular cells

3) goiter- swelling of thyroid gland due to hyperstimulation through TSH (TSH stimulates thyroid follicular cells to increase synthesis of thyroglobulin, happens when T3/T4 levels are low bc negative feedback inhibition is gone)


Describe the thyroid parafollicular C cells and parathyroid gland and the calcitropic hormones they produce

1) parafollicular C cells - round cells that lie outside the thyroid follicles, produce calcitonin which inhibits osteoclast function and impair Ca2+ reabsorption--> decreases plasma Ca2+ and P043-

2) Parathyroid gland - contains principal/chief cells- small cells with dark central nuclei that secrete PTH which activates osteoclasts --> increases plasma Ca2+;
also contain oxywhil cells which are larger and more acidophilic (function unknown); adipocytes also present


Describe the embryology, blood supply, and innervation of the adrenal gland

1) Embryology- adrenal cortex from mesodermal mesenchyme, adrenal medulla from migrated neural crest cells
2) arteriolar plexus on outer surface of gland - supplies all of adrenal gland through fenestrated capillaries and also separate medullary capillaries straight out to the medulla --> all drain into central adrenomedullary vein
3) Innervation - pregang SNS fibers on medullary cells which regulate secretion of epi/norepi


Describe the adrenal medulla:
1) types of cells
2) regulation of product secretion
3) effects of hormone products

1) Two types of chromaffin cells (ie post-ganglionic neurons): (1) dense granules and contains norepi (2) lighter granules and contains epi --> conversion from norepi--> epi regulated by cortisol from adrenal cortex (only direct connection between adrenal medulla and cortex);
closely packed clusters of cells, contains branches of large venous network

2) Stimulated by SNS tone eg stress - flight or fight response --> epi and norepi released into bloodstream to act on distant target cells

3) Epi binds mostly to beta1 adrenoreceptors - increases heart rate and contractility; Norepi mostly binds to alpha1 adrenoreceptors - induces vasoconstriction (splanchnic, renal, skin, genital);
both increase glycogenolysis, gluconeogenesis in order to generate energy


Describe the histology and function of the three zones of the adrenal cortex, including the regulation of product secretion:
1) Zona glomerulosa
2) Zona fasciculata
3) Zona reticulata

*adrenal gland covered by thick connective tissue capsule with trabeculae which contain blood vessels and nerves
*cells all have lots of SER --> all make steroids

1) Zona glomerulosa (15%)- rounded clusters of cells with darkly staining nuclei, secrete mineralocorticoids eg aldosterone; appears vacuolated due to lipid droplet content;
secretion regulated via RAAS

2) Zona fasciculata (80%) - large cells arranged as cords/columns and separated by sinusoidal capillaries, have light staining round nuclei; vacuolated cytoplasm indicates high lipid content, secrete glucocorticoids eg cortisol for stress/metabolism response;
secretion regulated via CRH --> ACTH from anterior pituitary

3) Zona reticulata (5%)- small cells with darkly staining nuclei, in irregular network with fewer lipid droplets in cytoplasm, separated by sinusoidal capillaries; secrete sex steroids ie androgens - androstenedione and DHEA which are converted to testosterone and estradiol in the peripheral tissues; *DHEAS is predominant adrenal androgen, secreted exclusively by the adrenal glands*
secretion regulated via CRH --> ACTH from anterior pituitary


Describe the effects of GH on lipolysis in fat, skeletal muscle, and the liver

1) Fat - GH promotes lipolysis, breakdown of fat produces FAs (eg ketoacids) and glycerol that skeletal muscles use for fuel (opposite action of insulin, which promotes lipogenesis)

2) Skeletal muscle - GH inhibits glycogenolysis, glucose uptake, and protein catabolism in skeletal muscle --> preserves plasma glucose levels
*GH is the only proglycemic anabolic hormone - insulin promotes glucose uptake, and glucocorticoids promotes protein catabolism*

3) Liver - stimulates gluconeogenesis in the liver (opposite action of insulin, which stimulates glucose uptake and inhibits gluconeogenesis)


What is the physiologic relationship bw glucose, insulin, and GH?

hypoglycemia --> GH secretion --> increased plasma glucose --> stimulates insulin secretion BUT GH impairs insulin sensitivity in liver and skeletal muscle--> decreases our sensitivity to insulin so we need to produce more insulin for same effect --> maintains blood glucose levels but could cause hyperinsulinemia (not a problem unless GH is chronically elevated)
*hyperglycemia leads to increase in insulin and downregulation in GH secretion*


How do GH and IGF-1 circulate in blood?

IGFBP and GHBP are carrier proteins produced in the liver, bind to IGF-1 and GH to aid in their delivery to target tissues, extending their half life and protecting them from being metabolized; IGF-1 and GH become bioactive when released from the binding proteins


Describe the regulation of bone growth and remodeling by GH and IGF-1

*GH itself does not have growth-promoting effects on bone- acts through production of IGF-1 and upregulating IGF-1 receptors*

1) Lengthening of long bones (only in children/adolescents) due to chondrocyte mitosis within epiphyseal cartilages, longitudinal growth stops when the epiphyseal plates fuse

2) GH stimulates osteoblast activity and promotes IGF1 expression in osteoblasts (E2 also does that)--> bone mineralization (deposition of Ca2+ as hydroxyapatite) in cortical and trabecular bone, happens throughout lifetime


Describe the secretion of GH. Which factors stimulate or inhibit this secretion?

1) Secretion - GHRH in hypothalamus --> stimulates acidophilic cells in anterior pituitary to secrete GH

2) GH stimulators: hypoglycemia, ghrelin, arginine, dopamine, metabolic stress eg sepsis, physical stress eg exercise, alpha2 adrenergic SNS tone, thyroid hormone

3) GH inhibitors: hyperglycemia, somatostatin, beta2 adrenergic SNS tone, increased FFA /GH/IGF1, aging


What are the endocrine tests for GH excess? deficiency?

*can use IGF-1 as reliable marker for GH
1) GH excess - suppression test - oral glucose tolerance test, give glucose load and measure GH levels (which should be LOW)

2) GH deficiency - simulation testing - either through injected insulin, exercise, arginine, GHRH- and measure GH levels (which should be HIGH)


Describe the diseases associated with GH/IGF-1 excess, including cause, symptoms, and treatment

1) Diseases: Acromegaly, Gigantism (in children)
2) Cause: pituitary adenoma
3) Symptoms: (gigantism only) - very tall; hyperglycemia, insulin resistance, DM, widened forehead hands feet nose jaw, hypertension due to increased aldosterone and fluid retention (chronic GH stimulates RAAS), ventricular hypertrophy and heart failure due to increased cardiomyocyte contractility and heart rate/CO
4) Treatment: somatostatin analogue (octreotide), GH-R antagonist, dopamine agonist (bromocryptine) *this is a quirk, physiologically dopamine stimulates GH secretion*


Describe the symptoms in children vs adult for GH deficiency, and treatment options

1) GH deficiency in children - short stature, central obesity
2) Adults- decreased bone density, central obesity, cardiovascular problems; dyslipidemia
3) Treatment - recombinant GH replacement therapy


I. Describe the biosynthesis of the steroid hormones from cholesterol

II. Give examples of each of the following families of steroid hormones:
A) Glucocorticoids
B) Mineralocorticoids
C) Androgens
D) Estrogens
E) Progestins

I. Steroid synthesis
1) Cholesterol circulates in blood stream attached to LDL receptor, is endocytosed into cell
2) Cholesterol --> pregnenolone in the mitochondria *rate-limiting step*
3) Pregnenolone transferred to smooth ER --> hydroxylated into specific steroid hormone depending on which adrenal cortex zone the cell is in e.g. only the zona glomerulosa has aldosterone synthase enzyme, CYP-17 only in zona fasciculata and reticulata
4) end product diffuses out of cell and into blood stream, androgens precursors have to be converted to active form in peripheral tissues

II. Steroid families:
A) Glucocorticoids - cortisol
B) Mineralocorticoids - aldosterone
C) Androgens - DHEA, androstenedione --> testosterone
D) Estrogens - estradiol E2
E) Progestins - progesterone, pregnenelone


Describe the hypothalamic-pituitary-adrenocortical axis and how it regulates steroid hormone biosynthesis in the adrenal cortex

Hypothalamic-pituitary-adrenocortical axis:
environmental stress (eg dehydration, fasting, emotion, exercise) --> stimulates CRH (corticotropin-releasing hormone) production in hypothalamus --> anterior pituitary secretes ACTH --> facilitates rate limiting conversion of cholesterol into pregnenolone (through enzyme CYP11A)-> creates end products --> androgens activated outside of adrenal cortex, cortisol binds to and is protected and distributed by CBG carrier protein, aldosterone rapidly metabolized
*cortisol has negative feedback on both CRH and ACTH production*


In the absence of environmental stress, when during the normal cicadian rhythm is ACTH secretion highest and lowest?

Highest after waking and right before eating (cortisol stimulates appetite), lowest right after going to sleep


What is Type 2 11-HSD and what is its function in cortisol metabolism?

Type 2-HSD - enzyme that converts cortisol to inactive form, found in liver --> inhibits cortisol from binding to mineralocorticoid receptors (which it can do bc it is structurally similar to aldosterone)


What is the metabolic function of cortisol (glucocorticoid) overall and in liver, muscle, and fat

1) Overall - increase blood glucose levels --> inhibits insulin action (minimizes glucose uptake in fat and muscle); promotes production of epinephrine in the adrenal medulla and glucagon (facilitates glycogenolysis)

2) Liver- anabolic effect - both gluconeogenesis and glycogen storage (maxes glucose production in liver, leads to hyperglycemia in Cushing's)

3) Muscle - catabolic effect - inhibit GHRH secretion, IGF1 synthesis --> protein breakdown to provide AA for gluconeogenesis --> can lead to muscle wasting; decreased sensitivity to insulin (inhibits glucose uptake in muscles)

4) Fat - induces lipolysis BUT stimulates appetite and caloric intake and thus induces lipogenesis in certain areas (abdomen, trunk, face)


What is the function of cortisol (glucocorticoid) on:
1) inflammation
2) immune response
3) bone
4) connective tissue + skin
5) kidneys
6) small intestine

1) Inflammation - most powerful anti-inflammatory, inhibits swelling and migration of leukocytes
2) Immune - inhibits T cells, used in organ transplants
3) Bone - stimulates osteoclasts/RANKL and inhibits osteoblasts to enhance bone resorption
4) Conn tissue - inhibits collagen synthesis --> bruising and stretchmarks
5) Kidneys - blocks Ca2+ reabsorption in distal nephron
6) Small intestine - impairs Ca2+ reabsorption


Describe the clinical disorders of the adrenal cortex
related to hyperfunction and hypofunction

1) Hyperfunction - hypersecretion of ACTH eg Cushing's syndrome- any rise in cortisol (most common cause is secondary cortisol excess i.e. pituitary adenoma - in which case it is Cushing's DISEASE). A) excess cortisol: (facial and abdominal obesity), insulin resistance --> DM, muscle atrophy, hyperglycemia (bc cortisol promotes glucose production in the liver), hypertension (cortisol can bind to mineralocorticoid receptor, causes peripheral vasoconstriction); B) excess androgens in females (body hair, voice deepening *because adrenal cortex is the major source of androgens in women (in men it is testes)*); C) treatment - remove tumor, cortisol/aldosterone antagonists e.g. ketoconazole

2) Hypofunction -deficiency in steroid hormones eg Addison's syndrome (most common cause is autoimmune destruction of adrenal cortex which is called primary Addison's). A) deficient cortisol: weight loss and fatigue, hypoglycemia, hyperpigmentation- normally cortisol negatively feedbacks on ACTH but bc its deficient, POMC (ACTH precursor) builds up and hyperstimulates melanocytes; B) deficient aldosterone (hypotension, hyponatremia, hyperkalemia); C) androgen deficient (reduction in pubic hair);
D) treatment - synthetic analogs eg prednisone and dexa (glucocorticoid), fludrocortisone (mineralocorticoid) --> lower ACTH and PRA, respectively (via negative feedback)

*secondary adrenocortical deficiency (due to low ACTH) would lead to loss in cortisol and androgens, NOT in aldosterone --> hypoglycemia, hypotension (cortisol increases peripheral resistance), NO hyperpigmentation (bc ACTH is low)*


What is hydroxyapatite?

essential mineral of bone matrix which contains Ca2+ and -P043-


What happens to serum levels of TSH and thyroid hormones T3, rT3, and T4 during illness, fasting?

1) TSH levels normal-low
2) T3 levels decrease due to increased 5-deiodinase activity
3) rT3 levels increase due to increased 5-deiodinase activity
4) T4 levels generally the same


1) What happens to thyroid hormones T3 and T4 in the bloodstream and then in target cells?
2) What is the significance of free and total thyroid hormone levels?

1) Bloodstream: T3 and T4 bind to plasma proteins (mostly TBG, some albumin) --> T4 more tightly bound --> smaller % is in free unbound form in circulation *T4 considered pro-hormone (circulating precursor) for T4 since it has longer half-life and can be converted into T3*

2) Target cells: Diffuse into target cell and bind to their hormone receptor in the nucleus onto HRE (hormone response element) in promoter region --> activate transcription of target gene (T3 binds with much greater affinity than T4)

3) free, unbound thyroid hormone is biologically active, majority of T3/T4 circulate in inactive bound form, use fT4 test to screen for thyroid disorders


What are the functions of thyroid hormone?

1) Raise basal metabolic rate (BMR) in every tissue type (except brain and testes) --> increased size and # mitochondria --> increased ATP --> increased 02 consumption --> increased body heat production

2) increased actin/myosin/ATPase/Beta adrenoreceptors (SNS) --> increased contractility/HR --> increased CO, also increased ventilation rate (both provide more 02 for aerobic metabolism)

3) Normal linear growth of children; required for synthesis of GH and IGF-1 --> bone growth and skeletal maturation --> otherwise cretinism

4) Stimulates GH/IGF1 (bone growth and mineralization), promotes bone remodeling (mature tissue resorbed, new bone formed) by increasing activity of osteoblasts and osteoclasts); *hyperthyroidism leads to increased bone resorption*

5) Maturation of CNS during perinatal period (before/after birth) --> otherwise mental retardation


Describe causes, symptoms, and treatment for the following:
1) Hypothyroidism
2) Sick euthyroid

1) Hypothyroidism:
A) Cause: most common is Hashimoto's thyroiditis - autoimmune response against TPO (thyroid peroxidase) enzyme --> low serum T3/T4 but high TSH + high levels of antibodies (that inhibit the enzyme); iodine deficiency in diet
B) Symptoms: decreased BMR, modest weight gain (lowered BMR + decreased appetite), bradycardia, low body temp/sensitivity to cold, hypoventilation, diastolic hypertension (clamp down on peripheral vessels to reduce heat leaving the body), goiter (due to hyperstimulation by TSH if problem is at thyroid level), reduced CO, lethargy/fatigue, myxedema/puffiness, mental slowing, anemia
Treatment: L-thyroxine T4 replacement therapy (curative);
*hypo and hyperthyroid fairly common causes of gonadal dysfunction*

2) Sick euthyroid:
A) Cause: acute illness, "hibernation" - body drops BMR to v low levels by decreasing thyroid hormone
B) Symptoms: low fT4, low TSH, low T3, but high RT3 bc body is shunting conversion away from active thyroid hormone


What are ways that thyroid hormone increase cellular energy expenditure in order to increase basal metabolic rate?

1) increase expression of Na/K ATPase
2) futile cycling of protein - stimulate both anabolic and catabolic pathways
3) facultative thermogenesis - short-circuits respiratory chain in brown adipose tissue --> energy lost to heat


Why do you have to measure albumin levels if someone has hypocalcemia?

Because the measurement we use is total calcium (bound to albumin, complexed to phosphate, and ionized):
hypoalbuminemia would decrease total Ca2+ levels but we are more concerned with bioactive ionized Ca2+ levels, which might be normal, so we add a correction factor to determine whether the hypocalcemia is legit
*most common reason for decrease in total Ca is hypoalbuminemia*


What is the difference between osteopenia and osteoporosis? What is osteomalacia?

Osteopenia - little bone loss

Osteoporosis - lot of bone loss

Osteomalacia - bone softening due to lack of Ca2+ or Vit D


Describe the process of bone remodeling?

1) Osteoblasts take up serum Ca2+ and P04 --> mineralizes into hydroxyapatite
2) Osteoblasts responsible for osteoclast differentiation (through RANKL) --> breaks down hydroxyapatite into Ca2+ and P04
3) Osteoblasts also produce osteoprotegerin that inhibits RANKL (thereby promoting resorption) - self regulation pathway


Explain the effect of PTH and how it is time and dose dependent

1) Acute or intermittent increase in PTH - is anabolic and promotes bone mineralization (can be used therapeutically) through promoting osteoblast differentiation

2) Continuous elevated levels - is catabolic and causes resorption of trabecular bone mass by stimulating RANKL


Where is CaSR expressed and what is its function?

Calcium sensing cell-surface receptor, changes activation motifs based on [plasma Ca2+]. Eg eu/hypercalcemia:
1) CaSR in apical membranes of proximal and distal nephrons - Increased filtered Ca2+ in the renal tubule --> inhibits enzyme --> down modulates Vitamin D synthesis in the proximal nephron
2) CaSR in parathyroid chief cells - Increased plasma Ca2+ (hypercalcemia)--> inhibits PTH secretion + inhibits chief cell proliferation + activates Vit D receptors which in turn inhibit PTH secretion, *Vit D upregulates CaSR to promote the PTH inhibition*


What is the role of FGF23 in dealing with hyperphosphatemia (e.g. in secondary hyperparathyroidism)?

FGF23 - downregulation of serum P04;
Elevated serum P04 (hyperphosphatemia) + calcitriol --> osteocytes secrete FGF23:
1) inhibits PTH secretion (which would free up phosphate by bone resorption)
2) blocks CYP enzyme vital for Vitamin D production (which would reabsorb P04 from proximal nephron)
3) promotes renal P04 excretion
4) promotes 24 hydroxylase which chews up Vit D and makes it inert

*estradiol/estrogen upregulates FGF23 (it also upregulates Ca2+)


What is DXA?

Scan for bone mineral density;
0 is good, negative numbers bad and imply osteopenia or osteoporosis if negative enough


Describe the function of the following in regulating Ca2+ and P04 synthesis:
1) Vitamin D/calcitriol
2) Calcitonin

1) PTH and/or hypophosphatemia --> CYP27B1 + calcidiol --> calcitriol --> stimulates Ca2+ and P04 reabsorption in the nephron, Ca2+ absorption from small intestine, bone resorption, can block PTH secretion (negative feedback loop)

2) Calcitonin: Rapid response hormone that impairs Ca2+ reabsorption and blocks osteoclasts--> decreases plasma Ca2+ and P04; BUT no long-term effects of pathologies (mostly useless)


Describe the function of the following in regulating Ca2+ and P04 synthesis:
1) Estrogen
2) Anabolic androgens

1) Estrogen E2 (Estradiol)- maintains bone density by:
A) small intestine - stimulating Vit D production --> Ca2+ and P04 absorption
B) bone - stimulates longitudinal growth and then growth plate closure, impairs RANKL and osteoclast differentiation,, promotes osteoclast apoptosis and osteoprotegerin and osteoblast differentiation

2) Anabolic androgens (Testosterone) - anabolic effects probably due to conversion of testosterone to estradiol E2 via aromatase/CYP19


Describe the following including cause, symptoms, and treatment:

Osteoporosis: wasting of bone matrix
1) Cause: age-dependent drop in E2, esp during menopause in women (ie ovarian failure)
2) Symptoms - decreased bone density in spine, hip, wrist --> potential fracture
3) Treatment - estrogen replacement therapy (ERT) *only if eligible (eg no breast cancer risk, history of cardiovascular disease)*, bisphosphonates (impair osteoclast activity) *most widely used drug for osteoporosis*, selective estrogen receptor modulator (SERM) (E2 agonist)


Describe the following including causes and symptoms:
1) Primary hyperparathyroidism
2) Secondary hyperparathyroidism

1) Primary hyperparathyroidism:
A) Cause: parathyroid adenoma causing hypersecretion of PTH --> increased Vit D production, increased resorption of Ca2+ and P04 from bone
B) Moderate Symptoms: hypercalcemia --> shortened QT interval on EKG, hyperphosphaturia/hypophosphatemia, patients usually asymptomatic, though may have bone and joint pain
C) Severe symptoms: hypercalcemia - causes constipation, hyperphosphaturia/ hypophosphatemia, bone loss due to increased bone resorption (due to chronic elevated PTH), oversaturated nephron Ca2+ resorptive capacity --> hypercalciuria --> formation of kidney stones + aberrant CaSR activity --> nephrogenic diabetes insipidus DI;
"stones, bones, groans"

2) Secondary hyperparathyroidism
A) Cause: Chronic kidney disease/renal failure --> loss of Vitamin D/calcitriol production --> loss of Ca2+ reabsorption from kidney and GI tract --> hypocalcemia --> induces production of PTH --> bone reabsorption to increase P04 and Ca2+ levels --> hyperphosphatemia (also caused by decreased PO4 excretion due to the renal failure)--> P04 mineralizes with Ca2+ to form calcifications --> decreased bioactive serum free ionized Ca2+ --> positive feedback on PTH and FGF23 --> cycle starts over


Describe cause, symptoms, signs, and treatment of hypocalcemia

1) Cause: hypoparathyroidism; chronic kidney disease or acute renal failure--> loss of calcitriol/Vitamin D synthesis
2) Symptoms: prolonged QT interval on EKG, muscle excitability
3) Signs: Trousseau's sign - carpal spasm when bp cuff is inflated (high specificity); Chvostek's sign - facial contraction when facial nerve is tapped near ear (low specificity)
4) Vitamin D, Ca2+ supplementation


Describe the signs and symptoms of the following:
1) Hyperphosphatemia
2) Hypophosphatemia
3) Rickets

1) Hyperphosphatemia: Cause - acute/chronic renal failure with GFR less than 30; Symptoms - impairs bone resorption and Vit D synthesis --> hypocalcemia, can also lead to metastatic calcifications (due to Ca2+ precipitation)

2) Hypophosphatemia: Cause - hyperparathyroidism or alcoholism; Symptoms - skeletal muscle weakness

3) Rickets: Cause - calcitriol/Vit D deficiency prior to closing of growth plates; Symptoms - hypocalcemia, hypophosphatemia


Describe causes, symptoms, and treatment for the following:
1) Hyperthyroidism
2) Graves

1) Hyperthyroidism:
A) Cause: most common is Grave's disease (autoimmune stimulation of TSH receptors by circulating antibodies); subacute thyroiditis, toxic goiter, hot nodule; diagnosed by low TSH and high serum T3/T4 ([T3]>>>[T4])
B) Symptoms: increased BMR, moderate weight loss (increased BMR + increased appetite), tachycardia/ palpitations, elevated body temp, sweating, excitability, systolic hypertension (heart pumping hard), goiter, dyspnea, osteoporosis (chronic increased TH stimulates bone resorption), oligmenorrhea, resting tremor
C) Treatment: tri inhibitor, thyroid ablation/removal

2) Grave's disease
A) Cause: autoimmune stimulation of TSH, genetic linkage, spontaneous remissions (Treat for 18 months)
B) Triad: hyperthyroidism, bulging eyes, dermopathy (red, swollen skin); v high uptake of radioactive iodine


Describe causes, symptoms, and treatment for the following:
1) Subacute thyroiditis
2) Multinodal goiter
3) Thyroid cancer

1) Subacute thyroiditis
A) Cause: thyroid inflammation caused by virus
B) Symptoms: hyperthyroid, hypothyroid, restored to normal after cells recover; often in postpartum women; low uptake of radioactive iodine
C) Treatment: block T3 production with PTU, beta blockers, or steroids

2) Multinodal goiter
A) Cause: living in iodine-deficient area (constant stimulation of TSH by low thyroid hormone levels); low TSH and elevated T4
B) Symptoms: hyperthyroidism if they're given iodine bc gland overreacts (Called JAD BASEDOW); hoarseness, afib
C) Treatment: radioactive iodine, surgery

3) Thyroid cancer
A) Cause: malignant "cold" nodule (does not produce thyroid hormone)
B) Symptoms: papillary (more benign), follicular (more aggressive), anaplastic (in elderly, v aggressive)
C) Treatment: radioactive iodine, T4 suppression (keep TSH low to remove stimulus for tumor to grow), surgery


List the steps in a radioimmunoassay (competitive binding assay) and how to interpret the results

1) Radioimmunoassay - measurement of hormone in biologic fluids; native and radiolabeled hormone compete for binding on antibody

2) Measure bound complexes in counts per min (cpm): higher cpm --> low concentration of native hormone, lower cpm --> high concentration of native hormone; compare cpm to standard curve to see amount of T4


List two examples of non-radioactive-based hormone assays

1) Enzyme immunoassay
2) Fluoroimmunoassay
3) Chemiluminescent assay


Describe stimulation and suppression tests in measuring endocrine function including physiologic rationale and an example of both

1) Stimulation test: uses positive feedback physiology e.g. apply GnRH and then measure levels of LH, TRH and measure TSH, etc.
A) Example - precocious puberty, apply GnRH in child and measure LH, if LH is above threshold implies premature neuroendocrine activation

2) Suppression test: uses negative feedback physiology e.g. downregulation of ACTH by cortisol, TSH by T3/T4, GH by hyperglycemia, aldosterone by oral salt load (bc it increases volume/BP which are the actual triggers)
A) Example - dex (potent glucocorticoid analogue) suppression test for Cushing's disease (ACTH excess) / syndrome (any rise in cortisol); low dose dex --> no response, high dose dex --> decrease in cortisol and ACTH bc feedback inhibition desensitized due to high levels--> Cushing's disease; if there is NO decrease --> Cushing's syndrome (primary cause, cortisol still being cranked out regardless of ACTH feedback)


Describe the anatomy of the wall of the scrotum. What is the function of the scrotum and the testes?

I. Skin --> dartos fascia with smooth muscle --> cremaster muscle and fascia --> parietal layer of tunica vaginalis --> serous cavity --> visceral layer of tunica vaginalis --> tunica albuginea (Buck's fascia)--> tunica vasculosa --> testis

II. The scrotum contains and protects the testes (exocrine - sperm - and endocrine - androgens - gland)


I. Where are the seminiferous tubules? Where are the Leydig cells?
II. Describe the components of the seminiferous tubules

A) 80% of testis is seminiferous tubules (~250); 1-4 seminiferous tubules in each lobule (subdivisions of the testes) -- site of sperm production
B)20% is Leydig cells in vascular connective tissue surrounding seminiferous tubules -- produce androgens (male sex hormones), primarily testosterone from androstenedione (enzyme only found in Leydig cells), when stimulated by LH from the anterior pituitary; *testosterone and andronstenedione the main sources of estrogen in men* also secrete TGFalpha, beta, IGF-1, and some estradiol E2; (lot of smooth ER, lipid droplets)

II. Outermost layer - peritubular myoid cells to propel sperm; tunica propria - vascular connective tissue that supports seminiferous epithelium; seminiferous epithelium - contains spermatogonia (stem cells) and Sertoli cells (keep stem cells nourished)


Describe the four phases of spermiogenesis (spermatid --> spermatozoa) and where they take place

Spermiogenesis- subdivision of spermatogenesis (1 spermatogonia --> 64 spermatozoa); spermatids are embedded in cytoplasm of Sertoli cells, near lumen in adluminal compartment
1) enzymes go from golgi to acrosomal sac
2) acrosomal sac flattens and forms cap around nucleus
3) acrosome and nucleus descend
4) maturation into spermatozoa
*contain dynein, Kartegener's syndrome leads to immotile sperm


What is the function and histology of the Sertoli cells?

1) Function: stimulated by both FSH and testosterone from Leydig cells
A) cytoplasm makes up the blood-testis barrier and separates maturing sperm away from immune system, also keeps testosterone levels high
B) provide physical support and nourishment to the spermatocytes
C) secrete activin (promotes release of FSH from anterior pituitary) and inhibin (inhibits release of FSH) --> FSH increases spermatogenesis and makes Leydig cells more sensitive to LH *inhibin exclusive to Sertoli cells, activin secreted by lots of other tissues*
D) secrete estrogen
E) produce androgen binding protein (ABP) -- keeps levels of testosterone high
F) secrete anti-Mullerian hormones (AMH) so Mullerian (female) reproductive ducts do not develop
G) secrete TGFalpha, beta, IGF-1 (autocrine-paracrine) -- stimulate mitosis

2) Histology - v tall columnar cells extending from bm to lumen


Describe the temperature regulation of the testis

Controlled by ANS;
dartos (smooth) and cremaster (skeletal) muscle contract when temperature drops to pull up testes;
countercurrent heat exchange bw testicular artery and venous pampiniform plexus


Describe the pathway of the spermatozoa

seminiferous tubules --> straight tubules --> Rete testis --> efferent ductules --> epididymis (storage site, sperm acquires motility) --> vas deferens--> ampulla (joined by seminal fluid) --> ejaculatory duct through prostate gland (joined by prostatic fluid) --> urethra through penis (lubricated by bulbourethral gland)


What are the male accessory glands? Describe functional anatomy + histology

1) Seminal vesicles - posterior aspect of bladder, mucosa + 2 layers smooth muscle; columnar epithelium + goblet cells; secrete seminal fluid rich in fructose into ampulla

2) Prostate gland - inferior to bladder, ejaculatory duct passes through; contains secretory (make prostatic fluid), basal (stem), and neuroendocrine cells; mature gland has prostatic concretions in the lumen; PSA antigen produced used for prostate screening tests

3) Bulbourethral (Cowper's) glands- found in UG diaphragm, secrete mucous to lubricate the urethra at start of sexual arousal


What are the zones of the prostate gland?

1) Transition - where ducts empty into urethra --> enlargement is benign prostatic hyperplasia (increase in # of cells) --> growth caused by DHT (synthesized in prostate from circulating testosterone)

2) Central

3) Peripheral - 70%+ of tissue and cancers arise here


Describe the histophysiology of erection and its stimulation by the ANS

1) flaccid penis - vascular spaces of erectile tissue eg corpus cavernosum contain little blood bc of anastamoses

2) erect penis - anastamoses closed in erect penis; nitric oxide released--> smooth muscle in arteries relaxed --> blood fills the corpus cavernosum --> rising blood pressure compresses venules against buck's fascia, reducing venous outflow --> traps blood and raises penis to erect position *erection is parasympathetic, ejaculation is sympathetic*


Describe the genetic basis of sex determination

Y chromosome contains SRY gene, which encodes TDF transcription factor -- regulates expression of genes for male gonadal devlpt; also need Androgen Receptor gene on X chromosome to sensitize ducts/genitalia to androgens


1) Describe gonadal cell equivalents in males vs females.
2) Describe the formation of genitalia in males

1) Gonads - indifferent gonad until Week 7; epithelium --> Sertoli (M) and granulosa (F), mesenchymal stromal cells --> Leydig (M) and theca (F);
spermatogonia formed at Week 9 and start secreting testosterone, stimulated by hCG (fetal testosterone precedes fetal LH secretion)

2) Genitalia - Week 9: testosterone (Leydig cells) triggers differentiation of Wolffian duct into epididymis, vas deferens, seminal vesicles; anti-Mullerian hormone (Sertoli cells) cause Mullerian duct (female gonads e.g. uterus) to atrophy;
Week 10: testosterone + 5 alpha reductase --> DHT --> penis, scrotum, urethra, prostate


Describe the hypothalamic -pituitary-testicular (HPT) axis. Describe how testosterone circulates in blood and what its active form is

1) GnRH (hypothalamus) --> simultaneous release of LH and FSH from anterior pituitary --> LH acts on Leydig cells to stimulate secretion of testosterone; tesosterone + FSH act on Sertoli cells to stimulate spermatogenesis --> testosterone and inhibin negatively feedback onto hypothalamus as well as pituitary

2) Majority of testosterone bound to SHBG or serum albumin, only 1% is freely circulating --> free + albumin-bound testosterone are active
*testosterone is predominant circulating androgen*; high levels of androgens (testosterone, DHEA, androstenedione) lead to lower levels of SHBG


What is the difference between testosterone and DHT in terms of their physiologic action as well as their biologic effects in the fetus, puberty, and adult

I. Physiologic action:
Most testosterone is converted into more active DHT (5x affinity for Androgen Receptor AR) in target tissues; when testosterone or DHT binds to AR, it goes into nucleus, dimerizes, and binds to androgen response elements (AREs) in the DNA to upregulate transcription

II. Biologic actions:
1) Fetal devlpt: (testosterone) masculinization of the Wolffian duct into the epididymis, vas deferens, and seminal vesicles; (DHT) devlpt of penis, scrotum, urethra, and prostate

2) Puberty: (testosterone + DHT + FSH/LH) devlpt of the testes; (testosterone + DHT + E2) spermatogenesis (with FSH/LH), negative feedback of HPT-axis; (testosterone + E2) bone growth by promoting GH secretion; (testosterone) larynx enlargement for deeper voice, increases size of muscle fibers; (DHT) devlpt of prostate, body hair growth, sebum formation (leads to acne)

3) Adults: (DHT) male pattern baldness; (testosterone) increases LDL and decreases HDL, stimulates RBC synthesis, initiates libido; (testosterone + E2) maintain bone mass; (testosterone + DHT + E2) spermatogenesis (with FSH/LH), negative feedback of HPT-axis


Describe the following clinical abnormalities in testicular function:
1) hypothalamic-pituitary disorders
A) Primary causes
B) Secondary causes

A) Primary causes of hypothalamic-pituitary disorders: Pituitary adenoma, infection, congenital gonadotropin deficiency (FSH, LH gene mutations), cause secondary disorders in androgen production and spermatogenesis (since there is no/decreased FSH/LH stimulation to the testes)

B) Secondary gonadotropin deficiency: Cushing's, exogenous glucocorticoids, fasting --> elevated cortisol inhibits LH secretion


Describe the following clinical abnormalities in testicular function:
2) primary gonadal abnormalities
A) Klinefelter's Syndrome
B) XX Male Syndrome
C) LH receptor mutation
D) Testicular failure
E) Androgen biosynthesis defects
F) Cryptochidism (failure of testes to descend)

A) Klinefelter's - XXY Male - high FSH/LH but low testosterone, small testes, boobs

B) XX Male - fragment of SRY translocated to X chromosome; variant of Klinefelter's

C) LH receptor mutation - autosomal recessive, XY have female phenotype and absent Leydig cells

D) Testicular failure - can be genetic, or acquired primarily from viral orchitis (from mumps virus), radiation, drugs or secondarily through illnesses eg. renal failure, AIDS, or chronic disease like cancer

E) Androgen biosynthesis defect - caused by genetic defects of genes in the biosynthetic pathway

F) Cryptochidism - fixes itself w/in one year, but associated with reduced fertility, testicular cancer, and inguinal hernias


Describe the following clinical abnormalities in testicular function:
3) Androgen resistance
A) Complete androgen resistance
B) Reifenstein's syndrome
C) 5 alpha reductase deficiency

A) Complete androgen resistance - most severe genetic defect in X-linked gene that encodes for Androgen Receptor --> XY are phenotypic women

B) Reifenstein's Syndrome - partial AR knockout--> XY is phenotypic man (normal Wolffian, no Mullerian duct features) but with boobs

C) 5 alpha reductase deficiency - testosterone cannot be converted to DHT --> XY is phenotypic man (normal Wolffian, no Mullerian) but boobs, small penis


Describe the following clinical abnormalities in testicular function:
3) Prostate cancer

3) Prostate cancer - Arises from changes in luminal epithelial cells; initially, tumors dependent on androgens (e.g. DHT) for growth but then switch to being androgen-independent (we dont know why or how)
*treat initially with anti-androgen compounds, androgen ablation


Describe the histology of the:
1) Ovary
2) Oviduct aka uterine tubes, fallopian tubes
3) Uterus
4) Cervix
5) Vagina

1) Ovary - simple cuboidal epithelium, then tunica albuginea layer of connective tissue; cortex- different stages of follicles; medulla has blood vessels + nerves

2) Oviduct - highly folded mucosa (fimbriae) contains simple columnar epithelium with ciliated cells and unciliated peg cells (secretes nutrition), then lamina propria, then 2 muscle layers, outer layer is serosa

3) Uterus - three layers = endometrium (decidua functionalis and decidua basalis), myometrium (v thick muscular layer), perimetrium (outer visceral covering)

4) Cervix = bottom of uterus, has endocervical canal with simple columnar epithelium which form glands, and extocervical canal with stratified squamous epithelium; external os is passage bw uterus and vagina

5) Vagina - stratified squamous, appears washed out bc lot of glycogen


ID the different stages of folliculogenesis:
1) Primordial follicle *ovarian follicular reserve*
2) Primary/preantral follicle
3) Secondary/antral follicle
4) Graafian/preovulatory follicle
5) Ovulation
6) Corpus luteum
7) Corpus albican

1) Primordial follicles - oocyte (arrested in Meiosis I) surrounded by single layer of flattened follicular pre-granulosa cells; oocyte secretes activin --> pituitary secretes FSH

2) Primary/preantral follicle - oocyte, zona pellucida (glycoprotein coat) develops; surrounded by 1+ layers of cuboidal cells, called granulosa cells bc they secrete things; basal lamina separates GC from theca interna cells (secrete androstenedione, progesterone, testosterone) and theca externa cells

3) Secondary/antral follicle - antrum forms, cavity filled with follicular fluid secreted by granulosa cells; layers of granulosa cells directly surrounding oocyte/zona pellucida called corona radiata

4) Graafian/preovulatory follicle - secondary follicle at its peak just before ovulation; antrum v large, oocyte sits on cumulus oophorus (hill of granulosa cells)

5) Ovulation - when LH levels peak; oocyte and zona pellucida and surrounding granulosa cells (corona radiata) released

6) Corpus Luteum - remaining follicular cell layer folds inward, breakdown of bm and invasion of blood vessels; granulosa (large, light) and theca (small, dark) cells become luteinized and secrete progesterone (lipid droplets, SER, etc)

7) If there is fertilization, hCG maintains corpus luteum; if not, then it degenerates into corpus albican (scar tissue so it appears washed out on LM)


What are atretic follicles? Describe the histology

Lot of follicles develop at one time but only one one is ovulated; the rest become atretic and degenerate via apoptosis


Describe the histological changes in the uterus during the menstrual cycle

1) Proliferative stage - under influence of estrogen, endometrium grows and glands are straight and narrow

2) Secretory phase - under influence of progesterone, glands widen and become corkscrew-like, glycogen accumulates in basal portion

3) Menstrual stage- if fertilization does not occur, corpus luteum degenerates, lose decidua functionalis (top layer of endometrium), arteries break down so there is blood in the lumen


Describe the histological changes of the mammary glands during different physiological states

Both ducts and alveoli glands are lined with cuboidal epithelial cell layer and myoepithelial cell layer, surrounded by dense irregular CT

1) Inactive - lots of ducts, lot of dense connective tissue

2) Proliferating mammary gland - under influence of estrogen and progesterone; less CT between secretory alveoli

3) Lactating mammary gland - under influence of prolactin, secretion of milk - pinkish stain in lumen of the alveoli is colostrum; oxytocin reacts on myoepithelial cells to help secrete milk into lumen and out


Describe the histology of the placenta including chorionic villic

1) Placenta = site of gas and metabolic exchange between maternal and fetal circulation;
maternal side has large and rounded decidual cells (provide nutrients), fetal side has amnion (simple cuboidal epithelium) and chorionic plate (where chorionic villi grow)

2) Chorionic villi - projections that maximize area for blood exchange; outer flat syncytiotrophoblast cells (secrete hCG) and cytotrophoblast cells (stem cells); contain fetal blood and outside the villi is maternal blood


Describe the causes and symptoms of the following renal tubule acidoses:
1) Type 2 RTA
2) Type 4 RTA

*RTA - metabolic acidosis due to impaired H+ secretion--> increased H+ and lower HC03-*
1) Type 2 RTA- normal AG (hyperchloremic) metabolic acidosis in proximal nephron; (A) Cause- defect in NHE3, Na/K ATPase, carbonic anhydrase; (B) Symptoms- glucosuria, hyperphosphaturia, Vitamin D deficiency, low urine pH, Na+ wasting --> hyperaldosteronism --> hypokalemia

2) Type 4 RTA- normal AG (hyperchloremic) metabolic acidosis in distal nephron; (A) Cause - aldosterone resistance bc of receptor defect; (B) Symptoms- hyperkalemia, volume depletion, hyponatremic, impaired urine acidification since NH4+ cannot be produced nor excreted due to high [K+]


Describe the mechanism of action of the following drugs:
1) "prils" eg lisinopril
2) Amlodipine, Verapamil
3) Propanolol
4) "sartans" eg losartan
5) Aliskeren
6) Tolvaptan
7) Dexamethosone, prednisone
8) Fludrocortisone
9) Luprolide
10) Clomiphene
11) Bromocryptine

1) Lisinopril: ACE inhibitor, prevents conversion of AI --> AII, used for hypertension

2) Amlodipine, Verapamil: Ca2+ channel blocker, used for hypertension, angina

3) Propanolol: Beta blocker, used to treat arrhythmia

4) Losartan: ARB, blocks angiotensin II AT1R receptor, used for hypertension

5) Aliskeren: renin inhibitor, used for hypertension

6) Tolvaptan: V2 receptor antagonist (AVP binds to V2 to stimulate H20 reabsorption through aquaporins), used to treat SIADH (euvolemic hyponatermia)/hypervolemia

7) Dexamethosone, prednisone: glucocorticoid analogues

8) Fludrocortisone: mineralocorticoid agonist

9) Luprolide: GnRH agonist --> disrupts GnRH pulsatility --> downregulates FSH secretion; used in assistive reproductive technology

10) Clomiphene: hypothalamic-pituitary ERalpha antagonist, used in assistive reproductive technology --> short-term GnRH agonist, long-term antagonist

11) Bromocryptine: dopamine receptor agonist, used to treat GH or PRL excess (acromegaly, hyperprolactinemia)


What are the possible causes and symptoms of nephrotic syndrome?

1) Cause: nephrin mutation that allows protein to be filtered

2) Symptoms: proteinuria --> hypoalbuminemia (low levels of protein in blood) --> edema (increased filtration out of capillaries due to decreased plasma oncotic pressure) + high cholesterol (dyslipidemia, triggered by hypoalbuminemia and decreased plasma oncotic pressure)


1) Describe the hypothalamic-pituitary-ovarian axis
2) Describe the roles of LH/FSH in follicular steroidogenesis pre and post ovulation

1) Neural input --> GnRH production stimulated in hypothalamus --> LH and FSH production in basophilic cells of anterior pituitary --> LH and FSH bind to cognate receptor, induce cAMP-PKA pathway which mobilizes cholesterol and enzymes --> steroidogenesis --> follicular steroids produce feedback on hypothalamus and pituitary

2) Preovulation:
LH stimulates theca cells to produce androstenedione (and a little testosterone); FSH stimulates preovulatory granulosa cells to convert these thecal androgens into estradiol E2 (and a little estrone E1) using CYP19 enzyme

*FSH and LH levels spike right before ovulation (LH>FSH)*

3) Post-ovulation (LH has luteinized the theca and GC within the corpus luteum):
LH stimulates luteinized granulosa cells to produce progesterone as well as estradiol, luteinized theca cells shift to producing progesterone
*theca cells do not express FSH receptors*


Describe follicular recruitment, selection, and atresia and the regulatory processes

*Follicular growth and generation process takes 3-4 months*
1) Recruitment - entry of primordial follicles out of reserve and into the growth phase to differentiate into primary follicles --> independent of gonadotropins (LH/FSH); in fact, during early follicular phase, low levels of LH and FSH are sustained by low levels of E2 (negative feedback on H-P axis); Secondary follicles and beyond DO require FSH/LH to further mature

2) Selection - happens in late secondary follicle stage, one gets chosen to become dominant follicle --> develops into Graafian/preovulatory follicle; selected follicle expresses more FSH receptors but also secretes Inhibin B which negatively feeds back on GnRH and FSH secretion in H-P axis

3) Atresia - breakdown of FSH-starved ovarian follicles via apoptosis


Describe the levels of the FSH, LH, E2, and P4 progesterone in the following phases of the menstrual cycle:
I. Follicular (Days 1-12; menstruation stops at Day 4)

I. Early-mid follicular stage: Low FSH, LH, progesterone, and serum E2 (E2 negative feedback on H-P axis which keeps FSH and LH low); Inhibin B produced by chosen preovulatory follicle inhibits FSH secretion through negative feedback on H-P axis
*cyclical stop and start pattern of growth for recruited follicles, stop growing when FSH is low*


Describe the levels of the FSH, LH, E2, and P4 progesterone in the following phases of the menstrual cycle:
II. Late follicular/Ovulatory (Days 12-14)

II. Late follicular/ovulation: E2 production by preovulatory follicle increases and peaks + Inhibin B secretion by preovulatory follicle decreases (lifts inhibition of activin)--> shifts to positive E2 feedback + production of activin and positive feedback on anterior pituitary --> increased FSH secretion--> FSH activates LH receptors in GC --> gonadatropin surge in both LH and FSH --> stimulates ovulation;
LH stimulates differentiation of the corpus luteum through luteinization of theca and granulosa cells
*LH considered the ovulation gonadotropin*


Describe the levels of the FSH, LH, E2, and P4 progesterone in the following phases of the menstrual cycle:
III. Luteal (Days 15-28)
In particular, how do E2 and P4 affect FSH and LH levels?

III. Luteal phase: Corpus luteum
A) Beginning: High E2 + rising P4 (produced by luteinized theca + GC in the corpus luteum) + Inhibin A (produced by luteinized GC) --> negative feedback on LH and FSH secretion

B) Rest of phase: Sustained elevated E2--> plugs into ERalpha in hypothalamus --> disrupts GnRH pulsatility --> inhibition of FSH>>LH;
profound peak in P4 by mid-luteal phase (shaped like a bell curve) --> plugs into PR in the hypothalamus --> disrupts GnRH pulsatility --> inhibition of LH >> FSH;
result is high E2, v high P4, low LH, low FSH

*increased P4 levels --> increase in basal body temperature (how women can see if they're ovulating)*

C) Menstruation: Dropoff in E2 and P4 levels at end of cycle leads to shedding of uterine lining, slight increase in FSH leads to follicular recruitment and growth


What are the differences between the role of ant-Mullerian hormone (AMH) in males vs females?

1) In males, AMH is secreted by Sertoli cells during fetal devlpt and inhibits formation of Mullerian ducts (eg uterux, cervix)

2) In females, AMH is secreted by granulosa cells in primary and secondary follicles --> fertility marker for healthy, growing follicles --> can be used to predict timing of menopause (AMH levels undetectable by the time a woman enters the menopausal transition)


Describe the endometrial changes during the menstrual cycle stages:
1) proliferative (follicular)
2) secretory (luteal) - early, mid, late

1) Proliferative: under influence of estradiol E2 --> induces expression of PR, ERalpha, growth factors --> regeneration and thickening of endometrium

2) Secretory:
A) Early - E2 + P4 --> angiogenesis
B) Mid- peak levels of P4 --> downregulate PR and ERalpha
C) Late - E2 and P4 withdrawal + receptors turned off (uterus assumes pregnant steroid-nonresponsive state)--> endometrium thickens and sheds --> menstruation --> uterus assumes non-pregnant responsive state and regenerates/repairs in preparation for next cycle
*P4 decrease mainly responsible for menstruation*


Describe two mechanisms of assistive reproductive technology:
1) promoting endogenous FSH
2) exogenous gonadotropins

1) Endogenous FSH: Clomiphene (ERalpha antagonist in hypothalamus) --> inhibits E2 negative feedback of GnRH --> GnRH spike --> increased FSH secretion --> formation of several dominant preovulatory follicles --> oocytes retrieved --> IVF --> embryo transfer --> give P4 into first semester so embryo implants and for uterine support

2) Exogenous gonadotropins: Luprolide (GnRH receptor agonist) --> disrupts GnRH pulsatility --> downregulates FSH secretion --> then exogenous recombinant FSH (rFSH) administered --> several dominant preovulatory follicles develop --> hCG (LH analog) given to induce ovulation --> oocytes retrieved IVF --> embryo transfer --> give P4 into first semester so embryo implants and for uterine support


Describe the function of the following enzymes in steroidogenesis:
1) CYP11A
2) CYP17
3) CYP21 (21-OH)
4) 17B- HSD
5) CYP19 (Aromatase)
6) Steroid sulfatase

1) CYP11A - catalyzes rate limiting step of cholesterol --> pregnenelone

2) CYP17 - used to produce glucocorticoids and androgens

3) 21-OH - used to produce mineralocorticoids and glucocorticoids, defect in congenital adrenal hyperplasia which shunts production towards androgens --> hyperandrogenemia

4) 17B-HSD - catalyzes androstenedione --> testosterone and estrone E1 --> estradiol E2

5) CYP19 i.e. aromatase - catalyzes testosterone --> estradiol E2 and androstenedione --> estrone E1; expressed in pre-ovulatory granulosa cells and in the hypothalamus (negative feedback on FSH>>>LH)

6) Steroid sulfatase - removes sulfate group attached to DHEAS to make it bioactive (DHEA androgen circulates with sulfate group attached in order to lengthen half-life)


Describe the steroidogenesis of early pregnancy - what hormones are released and what are their effects?

Placental GnRH --> stimulates trophoblast chorionic cells (fetal placenta) to produce hCG (potent LH analog)--> hCG takes over the role of pituitary LH, binds to LHR in corpus luteum --> stimulates secretion of P4 --> elevated P4 levels disrupt GnRH pulsatility --> decreased FSH and LH levels --> no folliculogenesis, ovulation, menstruation


What is the maternal recognition of pregnancy?

By end of first trimester, the control over the hormonal regulation of pregnancy (Eg progesterone and E2 production) shifts from corpus luteum --> trophoblast cells of the placenta
(*E2 produced by converting androgenic compounds*)


What hormones are produced in fetal and maternal steroidogenesis?

1) Maternal hormones: P4, ACTH, cortisol, DHEAS, and E3 *estriol is the main hormone of pregnancy*

2) Fetal hormones: CRH --> ACTH--> cortisol + DHEAS --> fetal liver --> placenta --> aromatized to E2 *DHEAS is the main source of E2 in 2nd and 3rd trimesters*; (there is steroid sulfatase in the placenta to make DHEAS bioactive; also 11B-HSD2 to make cortisol bio-INactive if too much is produced)

Goals: Fetal growth and development, timing of labor and parturition (ie birth)


What are the relative maternal serum levels of the following hormones during the stages of pregnancy and how they facilitate parturition (birth):
1) hCG
2) progesterone
3) estrogens (E1, E2, E3)
4) CRH
5) Relaxin *(produced by corpus luteum)*

1) hCG: produced by placenta, LH analog that promotes maintenance of corpus luteum in first trimester (CL produces progesterone which is needed to sustain the fetus), then drops off for rest of the time

2) Progesterone: increases until it peaks in third trimester, decreases before parturition bc role of progesterone is to maintain quiet myometrium; PRs also become less active which contributes to parturition

3) Estrogens: equal ratio of E2:E3 antagonizes ER; in third trimester, E3 levels increase --> activates ER --> promotes contractile myometrium

4) rise throughout pregnancy, peak at delivery; important for stimulating ACTH --> cortisol and DHEA --> fetal development, *mothers in premature labor given cortisol injections*

5) involved in softening the pelvic ligaments, cervical ripening (/dilation), rises in third trimester in preparation for labor


Describe the cardio-hemodynamic changes that occur throughout pregnancy in:
1) intravascular volume
2) heart rate
3) blood pressure
4) serum creatinine, BUN
5) 02 delivery

1) Intravascular volume - profound increase throughout pregnancy that plateaus in week 30
A) progesterone --> stimulates erythropoiesis
B) placental E2 --> RAS --> aldosterone
C) AVP --> H20 reabsorption

2) HR increases by ~10bpm --> increases CO

3) Blood pressure = CO x TPR; decreases overall bc vasodilation (TPR decreases) although CO increases, pressure lower more in diastolic compared to systolic; goes back to normal in week 36

4) GFR increases --> lower serum Cr, BUN

5) 02 delivery maintained bc cardiac output increases, and vasodilation --> increased perfusion to maintain high flow, low pressure environment for the fetus


Describe the pulmonary changes that occur throughout pregnancy in:
2) minute ventilation
What is the effect of these changes on ventilation?

What clinical problem could result?

1) FRC and ERV decrease due to diaphragm pushing upwards and increased chest wall compliance

2) Minute ventilation increases due to: A) tidal volume increase; B) progesterone stimulates medullary respiratory drive centers; C) increased metabolism leads to increased PaC02

3) Increased ventilation--> lowers PaC02 which: A) facilitates offloading of fetal C02; B) favors higher Pa02; C) facilitates maternal to fetal 02 transfer

4) low PaCo2 --> respiratory alkalosis --> compensation through decreased H+ secretion OR potential mixed disorder with metabolic alkalosis (but its okay during pregnancy)


Describe the factors that contribute to myometrial contractions during labor

1) inflammation of fetal membranes --> stop inhibition of prostaglandins --> contraction of the myometrium (+ cervical ripening/dilation)

2) placental CRH --> maternal adrenal cortisol --> promotes contractions

3) oxytocin, posterior pituitary hormone, causes smooth uterine muscle to contract

4) P4 withdrawal which removes contractile inhibition

5) increasing E3:E2 ratio --> Activates placental ER --> myometrial contractile proteins expressed

6) increased fetal growth --> puts tension on uterine wall --> stretch --> contraction


Describe the process of lactation (milk production) and milk let-down during gestation and post-partum

1) Gestation: prolactin PRL --> stimulates lactation (inhibited by dopamine in basal conditions);
E2 + P4 levels high --> promote development of breast tissue + inhibit milk let-down

2) Post-partum: E2 and P4 levels fall + suckling:
A) inhibits dopamine inhibition of PRL --> lactation *note that PRL can directly inhibit FSH and LH secretion, so hyperprolactinemia would cause amenorrhea*
B) release of oxytocin --> milk let-down
C) knocks out GnRH pulsatility --> impedes LH and FSH cylclicity


Describe the hormonal changes that take place during menopausal transition

1) depleted number of follicles --> E2 production declines + AMH levels are low + less inhibin B secreted --> suppression of FSH at anterior pituitary stops --> FSH levels rise (increased FSH:LH)--> accelerated exhaustion of follicular reserve (due to FSH and AMH)


Describe endometriosis, including:
1) pathogenesis
2) traits of the endometrial fragments
3) symptoms
4) treatment

1) Endometrial fragments that end up outside of the uterus, perhaps due to retrograde menstruation
2) Evade immune destruction, produce growth factors to make blood vessels, recruit neurons, increase CYP19 to keep E2 levels elevated, progesterone resistance to stay in proliferative phase of the menstrual cycle
3) Elevated E2 levels --> endometrial hypertrophy --> dysmenorrhea, dyspareunia, infertility
4) Treatment: Low-dose E2 + P4 contraceptive pill --> keep levels low without fluctuations that accompany normal menstrual cycle


Describe congenital adrenal hyperplasia (CAH) and treatment

defect in 21-OH, required to produce mineralocorticoids and glucocorticoids from cholesterol; without the enzyme--> steroidogenesis shunted towards producing adrenal androgens --> elevated DHEAS; also elevated ACTH due to lack of negative feedback from ACTH

treatment - synthetic glucocorticoids (dexa, prednisone) and mineralocorticoid (fluticasone)


Describe the criteria for diagnosis of PCOS as well as the symptoms and associated conditions

1) Diagnosis: Anovulation/irregular menses, hyperandrogenemia, exclusion of other hormonal disorders e.g. CAH, Cushing's *cystic ovaries can be present but not criteria for diagnosis*

2) Signs and symptoms: hirsutism (hair growth), acne, irregular periods, breast shrinkage, high LH and LH:FSH ratio, high insulin

3) Associated conditions: PCOS is a metabolic syndrome --> android obesity, dyslipidemia, hypertension insulin resistance --> DMII, risk of endometrial cancer bc of unopposed estrogen promoting endometrial growth


1) Why does ovulation not occur?
2) What problems can occur with hyperandrogenemia?

1) Because estrogen is maintained at constant level (old cells do not stop making E2, peripheral fat cells make E2 from androgen conversion):
no initial FSH rise in menses/early follicular phase --> no follicular growth and steroidogenesis (E2 levels need to fall for that) + no pre-ovulatory LH surge (need rapid E2 rise for that) --> no ovulation

2) High concentrations of androgens - inhibit aromatase activity, prevent dominant follicle selection and ovulation


Describe the following models for the pathogenesis of PCOS:
1) Insulin model
2) LH model
3) Adrenal model

1) Insulin model - android (abdominal, central) obesity --> Active adipocytes become insulin resistant --> hyperglycemia --> hyperinsulinemia --> insulin + LH have synergistic effect on theca cells --> increased androgen production --> inhibit LH and FSH secretion at H-P axis (through aromatization to estrogen)--> anovulation

2) LH model: anovulation/amenorrhea --> no corpus luteum formed --> no P4 produced --> loss of negative feedback on GnRH --> increased GnRH pulsatility favors LH over FSH secretion --> elevated LH levels --> stimulates theca cells to produce more androgens

3) Adrenal model: some women have adrenal cortical defect --> make too much DHEAS --> Steroid sulfatase in ovaries converts into androstenedione --> hyperandrogenemia


Describe the physiology behind the following treatments for PCOS:
1) weight loss
2) oral contraceptive pills (OCPs)
3) cyclic progesterone
4) clomiphene
5) metformin

1) Weight loss - reverses insulin resistance, decreasing the # of fat cells so you don't make as much estrogen from conversion of peripheral androgens in these cells

2) OCPs - contain E2 and P4--> suppress LH/FSH at H-P axis and E2 increases SHBG levels--> inhibits androgen production + more bound testosterone--> decreased free/bioavailable testosterone levels --> Restores cyclicity

3) Cyclic progesterone - provides cycle control, get withdrawal bleeds; prevents endometrial thickening/hyperplasia (suppresses PR and ERalpha receptors)

4) Clomiphene - blocks ERalpha at H-R axis --> stops LH and FSH inhibition --> higher FSH levels --> supports follicular growth and dominant follicle selection --> ovulation

4) Metformin - improves insulin sensitivity --> reduces hyperinsulinemia --> reduces androgen production by the theca cells --> ovulation


What are the criteria for becoming a candidate for hormone therapy to treat perimenopausal symptoms (eg night sweats, hot flashes)?

What treatment options are available for women who are candidates?

1) Criteria: Women who are not at elevated risk for breast cancer and have normal venous thromboembolism and cardiovascular disease risk

2) Uterus --> estrogen + progesterone (to protect endometrium);
Without uterus --> just estrogen