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Flashcards in Endocrine Deck (50):

Hormone circulation

-Released from granules in the glands into bloodstream
-Hormone must not be bound to protein to leave circulation (measure both free and bound)
-Hormones may be activated or inactivated after gland release


Endocrine regulation

-Direct vs indirect: is there an intermediary hormone or other mechanism involved? (indirect)
-Feedback vs feedforward: is response to a change after the change occurred (feedback) or before it occurred in anticipation for the change (feedforward)
-Controlling vs permissive: acutely causing the effect (controlling) or requires other machinery to have an effect (permissive)


Endocrine dysfunction

-If hormone A is controlled by hormone B, and hormone A level is abnormal, there could be 2 possibilities
-Either hormone B (effector hormone) level is abnormal and resulting in the abnormal A level (inappropriate relationship)
-If the effector hormone (B) is responding accordingly to the abnormal level of A, then it is a primary dysfunction


Measuring hormone amount

-Bioassay: measuring the effect of a crude extract
-Physiochemical assays: to detect unique physical and/or chemical properties of the hormone
Binding assays: immunodilution, immunocapture, fluorescence resonance energy transfer (FRET) all use Abs and hormone receptor analogs
-Immunodilution: add tagged hormone to assay (fixed receptors) then out-compete them w/ standard, measure amount needed to add
-Immunocapture: add hormone to assay, wash, then add tagged Ab for hormone to assay and measure how much Ab must be added
-Sandwich (FRET): Use 2 different Abs (both bind to hormone), one that requires 433nm to fluoresce (gives off 500nm) and one that fluoresces at 525nm but requires a different wavelength. When both are bound to hormone, the complex will use the 433nm and give off 525nm
-Things that can affect these tests: mutated hormones, degraded hormones, mutated/degraded binding proteins/Abs


Measure rates of hormone production

-Measure venous-arterial difference in concentration across the gland
-Measure plasma turnover (using tracer)
-Measure urinary excretion product


Contributions to obesity

-Difference btwn composition of fuel and the composition of food
-Relative amount of fat burned is less than the relative amount in food
-An RQ (respiratory quotient) greater than FQ (food quotient) can lead to obesity (quotients are amount of CO2 produced per O2 used)
-Thus a higher RQ means more glucose is being utilized as energy and not fat (RQ of glc = 1, RQ of fat = .7)


Feeding cycles

-During the absorptive state carbs are the major source of energy. Proteins and glycogen are synthesized. Triglycerides are stored in adipose using G-3-P to make TAGs (either glucose or glycogen used to make G3P b/c adipose lack glycerol kinase)
-During this state carbs and AAs can be used to make fats via "anaerobic" glycolysis (thru AcCoA)
-Postabsorptive state: FAs are used for energy (glc is spared) except in nervous tissue and RBCs. Net release of FAs from adipose. Glc made in liver via GNG and glycogenolysis. Proteins are degraded and AAs converted into glc
-Starvation: Glc stores only sufficient for one day, fat stores can last over a month. Brain converts to ketone bodies


Insulin in absorptive state

-Promotes glc uptake in muscle, reduces utilization of fat
-Promotes glycogen synthesis
-Promotes AA uptake and protein synthesis
-Promotes TAG storage in adipose (increased glc entry and inhibition of HSL)
-Hyperinsulemia can be a cause of obesity


Regulation of insulin release

-Parasympathetic nerves from vagus, also release of incretins from GI distinguishes glc rise from food from a glc rise from hepatic output
-Sympathetic nerves inhibit insulin release, also epinephrine binds to mostly alpha adrenergic receptors (different from most tissues, which usually express more beta adrenergics)


Insulin resistance

-For insulin to work it must be pulsatile; constant activation leads to desensitization
-Hyperinsulemia leads to insulin resistance


Glucagon in the post absorptive state

-Fall of glc causes release of glucagon, which promotes FA release from adipose, and promotes glc release from liver (opposes insulin)
-Control: epinephrine promotes secretion
-Epinephrine also acts on muscle to increase glycogenolysis and lactate efflux. It promotes blood flow through adipose, lipolysis, and FA efflux
-Lack of epinephrine can lead to hypoglycemia


Signals to CNS about food

-Ghrelin is released from the stomach containing an O-linked octanoyl side group, which is required for action on its CNS receptor
-Lesions to lateral hypothalamus cause anorexia, lesions to the ventromedial hypothalamus cause voracious overeating and obesity
-CNS controls adipose tissue in part by vagal control of insulin release
-Leptin is a protein that makes you want to eat less. Animals w/ leptin deficiency or mutated leptin receptors eat much more and are obese (works on the CNS)
-Leptin is from white adipose, leptin deficiency or resistance can lead to obesity


Hypothalamus regulates endocrine functions

-Does so by portal system to pituitary (anterior only, posterior thru neurons)
-Releasing hormones released by hypothalamus cause pituitary to release effector hormones, which act on certain organs (peripheral glands). These glands in turn release other hormones which have activity throughout the body
-Negative feedback loops regulate endocrine activity (both to hypothalamus and pituitary)
-Releasing hormones from hypothalamus have ultra short loop (inhibit release of releasing hormones from the hypothalamus)
-Pituitary hormones have short loop and inhibit releasing hormone release from hypothal
-Peripheral gland hormones have long loops and act on both releasing hormones in hypothal and effector hormones from pituitary


Dysregulation of endocrine signaling

-Can be primary dysfunction (only the peripheral gland is abnormal). In this case both the pituitary and the thypothal hormones will be compensating by changing levels appropriately
-Can be secondary dysfunction (either @ hypothal or pituitary). Distinction depends on the abnormalities of the other levels
-If the hypothal is abnormal, both down stream targets (pituitary effector hormones and peripheral gland hormones) will have abnormal values
-If pituitary is abnormal only the peripheral gland hormones will be abnormal, but the hypothal releasing hormone will change accordingly in an attempt to compensate (this is an inappropriate relationship)


Organization of the adrenal gland

-Outer 80% is cortex, which synthesizes steroids (aldosterone, cortisol, androgens)
-Inner 20% is medulla which synthesizes catecholamines (epinephrine, norepinephrine)
-Sympathetic activation of gland results in synthesis and release of catecholamines


Effects of epinephrine

-Epinphrine binds to both alpha and beta adrenergic receptors, but binds better to beta
-The effect of epinephrine on a tissue depends on: the ratio of a/B receptors and the concentration of epinephrine


Examples of different effects of epinephrine

-In the pancreas there are much more alpha receptors than B receptors. Thus epinephrine mostly binds to the a receptors, causing decrease in both glucagon and insulin release
-In blood vessels a receptors lead to vasoconstriction and B receptors lead to vasodilation
-There are many more a receptors in peripheral CVS, so @ high concentrations of epinephrine most of the receptors bound are a and vasoconstriction results
-But at low concentrations of epinephrine, most of it is bound to B receptors due to the higher affinity, and vasodilation results


Tumors of the adrenal medulla

-Pheochromocytoma leads to excessive release of epinephrine, which can lead to other problems like hypertension


Regulation of steroid hormones synthesis

-Steroids are synthesized from cholesterol (C21 and C19 steroids). These are not stored but made upon activation of cAMP
-Steroid hormones are glucocorticoids (cortisol), mineral corticoids (aldosterone), androgenic (the C19 hormones, no role in men due to testosterone from testes)
-Androgenic hormones are converted to testosterone by peripheral tissues and has effects only in women. Made in the cortex in zone reticularis


Adrenal mineralcorticoids

-Made in cortex, zona glomerulosa
-Acts on kidneys to retain Na and water
-Kidneys sense decrease in blood volume and release renin, which activates angiotensin I into active form, angiotensin II
-Angiotensin II stimulates release of aldosterone from adrenal glands
-Aldosterone promotes Na and water retention, K excretion
-Adrenal adenomas can constitutively secrete aldosterone, leading to depressed renin levels


Adrenal glucocorticoids

-Made in cortex, zona fasciculata
-Most is transported through blood on binding proteins
-There are 2 receptors, type 1 produces mineralcorticoid response. Type 2 produces glucocorticoid response
-Type 1 binds mineral and glucocorticoids w/ equal affinity
-Type 2 only binds cortisol well. Cortisol can be converted into cortisone (inactive form) by 11B-HSD. Cortisone cannot bind type 1 or type 2
-Conversion is reversible and in some tissues one form is favored and in others tissues the other form is favored


Ex of different tissues favoring different glucocorticoids

-Most tissues favor the conversion of cortisone into cortisol (active), such as in the liver (it promotes gluconeogenesis and glycogen synthesis)
-Tissues that aldosterone targets, like kidney, colon, and sweat glands, favor cortisone (inactive), so that the mineralcorticoid receptors are available
-Glycyrrhizic acid (GA) inhibits 11B-HSD and can be found in licorice


Effects of cortisol

-It is a permissive hormone, it enhances the effects of some hormones, inhibits the effects of others
-It can potentiate the glycogenolytic effect of glucagon
-It inhibits insulin promotion of glc uptake and glycogen synthesis in tissues except brain and heart
-Acts synergistically w/ epinephrine to increase blood glc and FA levels (diabetogenic)
-Promotes gluconeogenesis, and during the absorptive state promotes glycogen synthesis in liver
-Required for the lipolytic effects of other hormones
-Prepares you for stress (needed prior to stress): promotes storage during absorptive stage, promotes breakdown during FOF
-It is used to reduce immune and inflammation response (decreases number of circulating T cells, their ability to migrate to a site of infection, and their function)


Regulation of cortisol

-Peaks at morning, lowest at sleep
-Main regulator is ACTH from the pituitary
-Pituitary releases ACTH in response to CRH (corticotropin-releasing hormone) release from hypothal
-Prolonged stimulation by ACTH causes hyperplasia of adrenals
-Prolonged use of cortisol causes atrophy of adrenals b/c of the inhibitory affect on ACTH release
-Cortisol feeds back to pituitary to inhibit ACTH release and on the hypothal to inhibit CRH release
-ACTH feeds back on the hypothal to inhibit CRH release


Cortisol excess and deficiency

-Excessive release of cortisol is Cushing's syndrome, if it is due to pituitary tumor causing high levels of ACTH it is Cushing's disease
-The syndrome may arise from adrenal neoplasm
-These lead to hypertension, obesity, striae (stretch marks)
-If a patient has high cortisone but low ACTH, the problem is in the adrenals, not the pituitary (probably adrenal tumor)
-Cortisol insufficiency is Addison's disease and can be due to infectious and autoimmune, cancer of the adrenals, adrenal hemorrhage, shock, sudden withdrawal of coritsol, pituitary insufficiency, TB


Thyroid hormone

-Releases thyroid hormone T4 and T3 (T3 more potent)
-Synthesized in thyroid colloid within the follicles
-Iodine is trapped within the colloid by thyroglobulin, then thyroid peroxidase adds the iodines to thyroxine to make T4
-T3 made by deiodination
-RT (inactive form) can also be made from T4 thru deiodination


Regulation of thyroid hormone secretion

-Hypothalamus releases TRH (thyroid releasing hormone) on pituitary, which releases TSH (thyroid stimulating hormone)
-TSH acts on thyroid and causes release of T3 and T4
-T3/4 feed back on pituitary and hypothal to inhibit release of TSH and TRH, respectively
-TSH also feeds back to hypothal and suppresses release of TRH


Effects of T3/4

-Increases metabolic rate, heat production, uncoupling in brown fat, Na-K ATPase
-Increases effectiveness of catecholamines
-Increases ventilation and cardiac output
- Increases food intake and mobilization of energy reserves
-If elevated will decrease body mass (muscle and adipose)



-If present at birth and not correct can lead to retardation and dwarfism (cretinism)
-Can be caused by iodine deficiency, chemical inhibition of trapping, goitrogens, autoimmune disease (Hashimoto's thyroiditis), TSH insufficiency
-Can lead to proliferation of thyroid cells causing hyperplasia and goiter (TSH will be low)



-Manifests as weight loss despite increase food intake, discomfort in warm environment, fever, tachycardia, tremors, nervousness
-Causes: excess TSH, thyroid cancer, graves disease (Abs bind to and activate TSH receptor, can cause goiter and bulging eyes or exophthalmos)
-Goiter can be due to high TSH or graves disease


Circulation and measuring thyroid hormone

-Circulates bound to TBP (thyroxine-binding protein, most of T3/4 is not free)
-In hypo/hyperthyroidism, total and free T3/4 is low/high and TSH will be low/high, but binding proteins will be normal
-Some substances will cause high TBP (estrogen, drugs, ect). This leads to low free T3/4 and pituitary compensates by increasing TSH release. After equilibrium is re-established, there is high TBP, high total T3/4, normal free T3/4 (most was bound by TBP), normal plasma TSH, and normal thyroid
-Some substances will cause low TBP (glucocorticoids, testosterone, ect). Leads to high free T3/4 and pituitary compensates by decreasing TSH release. After equilibrium is re-established, there is low TBP, low total T3/4, normal T3/4 (will be free b/c low TBP), normal TSH, and normal thyroid



-Secreted by pituitary
-Promotes milk secretion and maternal behavior (synthesized in lactotrope cells)
-Controlled by suckling on breast (positive feedback), release of dopamine by hypothalamus (inhibits prolactin release)
-Negatively regulated by high levels of gonadotrophs (estrogen, FSH, LH)


Lutenizing hormone (LH)

-Secreted by pituitary
-Major effects in females: stimulates ovulation
-In males: stimulates testosterone secretion
-Controlled by GNRH (gonadotropin releasing hormone) release by hypothal
-Release of GNRH controlled by prolactin levels, and negative feedback of estrogen/testosterone on hypothal


Follicle stimulating hormone (FSH)

-Secreted by pituitary
-Stimulate ovarian follicle growth in females
-Stimulates spermatogenesis in males
-Controlled by GNRH (gonadotropin releasing hormone) release by hypothal
-Release of GNRH controlled by prolactin levels, and negative feedback of estrogen/testosterone on hypothal


Hyper and hypoprolactinemia

-Hypoprolactinemia can result from pituitary damage (causes failure to lactate)
-Hyperprolactinemia often results from prolactinoma (most common pituitary tumor
-Rx of hyperprolactinoma is usually a D2 agonist to inhibit prolactin release


Posterior pituitary

-ADH (vasopressin): promotes water retention in kidneys
-Central diabetes insipidus caused by failure to secrete ADH
-Oxytocin: acts on breast to eject milk and on uterus to cause contraction


Growth hormone

-Also called somatotropin, not highly conserved btwn species
-synthesized and stored in anterior lobe of pituitary (10% of weight)
-Released in pulsatile manner, spares glc (decreases glc uptake) and increases availability of FA (diabetogenic, anabolic), promotes AA uptake and protein synthesis
-Promotes the growth of limbs and organs


IGF (insulin-like growth factors)

-Mediate some effects of GH
-Similar to insulin but contains a C-peptide that is removed for insulin
-Have similar effects to insulin. Type 1 receptor binds IGF1 strongly (similar structure to insulin receptor but doesn't bind insulin or IGF2)
-Has a substantial effect on insulin transport into cells only during fasting stage
-Rx of hypophysectomized rates w/ IGF1 restores growth (but not IGF2)


Control and effects of IGF1

-GH released by pituitary acts on liver which releases IGF1
-IGF1 increases bone growth (cell size and number), and growth of organs through the same mechanisms
-GH is diabetogenic b/c it decreases glc uptake (increases its plasma concentration), and increases gluconeogenesis
-GH also increases lipolysis, AA uptake, protein syn, and IGF1/2 release


Regulation of GH secretion

-Hypothal releases growth hormone releasing hormone (GHRH), stimulating GH release from pituitary (via Gs GPCR)
-Somatostatin acts to oppose GHRH and inhibits GH release (somatostatin overrides GHRH)
-Somatostatin acts via Gi GPCR (can also be found in pancreas where it suppresses insulin release)
-GHRH feeds back on the hypothal via negative ultra short feedback loop
-GH feeds back on hypothal to increase somatostatin release
-IGF feeds back on pituitary to decrease GH release (negative feedback)
-IGF also leads to high blood glc, which will increase somatostatin release from hypothal and inhibit GH release


Temporal release of GH

-Feeding decreases circulation of GH
-Insulin induced hypoglycemia can be used to test for normal GH release response


Excess growth hormone release

-Pituitary tumors can lead to hypersecretion of GH
-These retain the differentiated function of somatotrophs and do not metastasize
-If hypersecretion occurs before the bony epiphyses close it leads to giantism (bone growth in legs and arms)
-If hypersecretion occurs after the epiphyses close, it leads to acromegaly (bone growth in finger, toes, gads, feet, jaw)
-Rx is using GH analog to inhibit GH binding to receptor
-GH causes receptor dimerization (needed for activity), and binding of an analog prevents dimerization of the receptor


Lack of growth hormone

-Leads to dwarfism when occurring in children
-In adults it is not known to cause any serious problems
-Mutations in GH receptor lead to a low response to GH
-Rx is supplementation of IGF when there is mutation in GH receptor (laron syndrome)
-Rx is supplementation of GH when there is low GHRH secretion


Ca and PO4 homeostasis

-Very tight control of blood Ca, PO4 not as tightly regulated
-99% of Ca in bone, 85% of PO4 in bone
-Gut used for regulation of absorption of Ca and PO4
-Kidney used for regulation of reabsorption of Ca and PO4
-Bone reservoir for both (can be broken down and released)


Vitamin D

-Synthesized in skin by sunlight and heat (non enzymatic) form 7-dehydro-cholesterol
-Vit D transported to adipose (reservoir) and liver to begin activation. Liver adds an OH to the 25 position to make 25(OH)-Vit D
-If there is a Vit D deficiency, the 25(OH) form will be decreased (not the 1,25 form since that is active and will be preferentially made). Vit D deficiency leads to rickets
-25(OH) Vit D then is brought to kidney and either converted into active form 1,25(OH) Vit D or inactive form 24,25(OH) Vit D
-1,25(OH) Vit D can be converted to 1,24,25(OH) Vit D in kidney, which is also inactive


Effects of Vit D

-Promotes uptake of Ca and PO4 form gut, promotes resorption of bone
-Together these two things will increase Ca and PO4 blood levels
-This can lead to crystallization, so there is an effect on kidneys too
-Vit D increases reabsorption of PO4, but Ca reabsorption is unchanged (unless blood Ca gets too high, then it will be excreted)
-Vit D deficiency leads to a compensatory elevation of PTH, which promotes the conversion of Vit D to 1,25(OH)
-Net effect is both raised Ca and PO4


PTH (parathyroid hormone)

-Plasma Ca is principle regulator of PTH secretion from parathyroid gland
-As Ca levels fall, PTH secretion will rise
-PTH acts on bone to promote resorption (increasing Ca and PO4), it also increases 1,25(OH) Vit D so there is an indirect increase in gut absorption of Ca and PO4
-Also acts on kidneys to increase PO4 excretion (phosphaturic) and inhibit Ca excretion
-Net effect is increase in Ca and decrease in PO4



-Can result from PTH secreting tumors, deficiency in Vit D



-Due to lack of sufficient PTH
-Psuedohypoparathyroidism (PHP) resembles milkd hypoparathyroidism, due to low expression of the GPCR receptor on the thyroid


Summary of PTH and Vit D

-PTH and Vit D acutely increase plasma Ca
-PTH lowers plasma PO4 (via renal excretion), while Vit D increases it (no effect on renal excretion)
-Low Ca leads to increase in PTH, which leads to an increase in Vit D. Together there is little change in PO4 and increase in Ca
-Low PO4 leads to increase of Vit D, which increases Ca, which decreases PTH. Low PTH leads to decrease in Ca reabsorption and there is little change in Ca, with an increase in Ca