Physiology pptx flashcards and objectives

What are hormones?

• chemicals produced by endocrine glands

• transported by the vascular system to alter the function of distant target cells (endocrine communication)

What is a target cell? How do hormones affect target cells?

• influence the production of enzymes or the rate of enzymatic reactions

  • hormones do not initiate reactions (basal reaction levels occur without the presence of hormones)

What physiologic functions are regulated by the endocrine system?

• Metabolism

  • energy balance: insulin, glucagon, cortisol, epinephrine, thyroid hormone, growth hormone

  • mineral balance: parathyroid hormone, calcitonin, angiotensin, renin

• Growth

  • growth hormone, thyroid hormone, insulin, estrogens, androgens

• Reproduction

  • estrogens, androgens, progesterone, luteinizing hormone, follicle-stimulating hormone, prolactin, oxytocin

Paracrine communication

• involves a chemical that is synthesized & released by a cell

• the chemical diffuses through the surrounding extracellular fluid

• the chemical binds receptors on & alters the function of nearby cells

Autocrine communication

• involves a chemical that is synthesized & released by a cell

• the chemical diffuses through the surrounding extracellular fluid

• the chemical binds receptors on & alters the function of the same cell (or a nearby cell of the same type)

Neurocrine

• involves the release of neurotransmitters into a synaptic cleft to affect a postsynaptic cell

Neuroendocrine

• involves a chemical (neurohormone) that is synthesized & released by neurosecretory neurons

• the chemical is transported by the vascular system to alter the function of distant target cells

Exocrine

• involves a chemical that is synthesized & released by a glandular cell

• the chemical is transported via a duct to alter the function of distant target cells

Pheromonal

• involves a chemical that is synthesized & excreted by 1 animal

• the chemical externally influences the behavior or development of other animals

How are the endocrine and nervous systems similar?

• both are responsible for coordinating & regulating physiologic systems

• both utilize chemical messengers

  • hormones (endocrine)

  • neurotransmitters (nervous)

  • neurohormones (neuroendocrine)

how does the endocrine and nervous system differ?

timing

• neurocrine communication involves relatively short, rapid signals & responses (milliseconds to seconds)

• endocrine communication involves relatively slow signals

  • however, endocrine communication induces prolonged responses (minutes to days) in the target cells

How are protein and peptide hormones synthesized?

inactive precursors to protein/peptide hormones are synthesized via:

                      -transcription

  -synthesis of mRNA using a DNA template (RNA & DNA sequences are complimentary)

                      -translation

  -process of peptide synthesis carried out by mRNA, tRNA (transfer RNA), & ribosomes

  -amino acid sequence is determined by the sequence of nucleotides in mRNA

  -each tRNA molecule delivers a specific amino acid to a specific mRNA sequence 

After translation, are these proteins biologically active?

  -no, inactive precursors to protein/peptide hormones undergo 1 or 2 steps of…..

Post translational modification

post-translational modification – RER

• hormone precursors are secreted into the interior of the RER

  • peptidases within the RER wall cleave AAs from the precursor molecule creating a new protein/peptide

post-translational modification – Golgi

• hormone precursors enter the Golgi apparatus via membrane fusion

  • peptidases within the Golgi apparatus wall cleave AAs from the precursor molecule creating a new protein/peptide

post-translational modification – secretory vesicles 

• hormone precursors leave the Golgi apparatus via membrane fusion

  • peptidases within the newly-created vesicles cleave AAs from the precursor molecule creating a new protein/peptide

preprohormones

-protein precursors of hormones

  -undergo 2 steps of post-translational modification (RER and/or Golgi and/or secretory vesicles)

  -preprohormone → prohormone → hormone

prohormones

protein precursors of hormones

  -undergo 1 step of post-translational modification (RER or Golgi or secretory vesicles)

  -prohormone → hormone

How is release of protein/peptide hormones regulated?

secretory vesicles (granules)

How are secretory vesicles formed?

• occurs when hormones leave the Golgi via vesicle budding (type of membrane fusion)

  • many hormones are in their final, active form within the secretory vesicles

  • some secretory vesicles contain prohormones & peptidases necessary to produce active hormone

How are protein and peptide hormones secreted?

exocytosis of secretory vesicles

what are the two types of secretion for protein and peptide hormones?

• low levels of secretion occurs continuously (basal secretion)

• increased secretion occurs in response to a cellular signal (regulated secretion)

How does calcium mediate exocytosis of secretory granules?

secretory vesicles dock on the cell membrane due to the intertwining of membrane proteins

-synaptobrevin on the vesicle membrane

-SNAP-25 & syntaxin on the inner surface of the plasma membrane

Following an influx of Ca²⁺ into the cytoplasm

  → Ca²⁺ binds to synaptotagmin (another protein located on the vesicle membrane)

  → stimulates fusion of the vesicle membrane with the plasma membrane

  → hormones within the vesicle are released into the extracellular space (exocytosis)

  -the vesicle membrane is recycled & re-filled following exocytosis

What are steroid hormones derived from and what is their basic structure?

-lipophilic molecules with a 4-ring, 17-carbon backbone

  -majority are derived from cholesterol

  -can also be synthesized using acetate

How do cells obtain and store cholesterol for steroid hormone synthesis?

-low-density lipoproteins (LDLs)

  -enter cells via membrane receptors (receptor-mediated endocytosis)

  -degradation of LDLs within the cells by lysosomal enzymes frees cholesterol

  -cholesterol that is not immediately used for steroid synthesis is stored as esters in lipid droplets in the cytoplasm

What is the rate limiting step of steroidogenesis? How is it mediated?

-for steroid synthesis, cholesterol is transferred from the outer to the inner mitochondrial membrane

  -cholesterol cannot cross the aqueous space between the mitochondrial membranes without protein assistance

  -this process is primarily mediated by StAR (steroidogenic acute regulatory protein)

How is cholesterol converted to pregnenolone?

-the side chain is then cleaved from cholesterol in the mitochondria

  -this process is catalyzed by the cytochrome P450scc (side chain cleavage) enzyme

  -yields pregnenolone 

Where do the enzymatic modifications of pregnenolone occur during steroid hormone synthesis?

-subsequent enzymatic modifications of pregnenolone occur within the mitochondria or smooth ER

  -steroidogenic enzymes are localized within the mitochondrial & smooth ER membranes

  -the control of steroid hormone movement between these 2 organelles is poorly understood

What determines which steroid hormone is ultimately synthesized by a cell? 

-enzymes which are present 

  -example: androgen-secreting cells

  -different enzymes are present for the formation of pregnenolone, progesterones, & eventually androgens

  -these cells lack the enzymes which convert androgens to estrogens (unlike estrogen-producing cells)

Can steroid hormones be stored?

-no mechanisms are available for intracellular storage of steroid hormones

  -unable to regulate release

-therefore, hormones are released from the cell immediately after synthesis

  -the rate of release is determined solely by the rate of synthesis

How are steroid hormones exported from the cell?

  -the small, lipophilic structure of these hormones allows for simple diffusion across cell membranes

Which hormones are derived from enzymatic modification of tyrosine?

catecholamines

Are catecholamines “made to order”?

-no, stored in secretory vesicles

-released via exocytosis of secretory vesicles

How are thyroid hormones synthesized?

coupling & iodination of 2 tyrosine molecules 

How are thyroid hormones stored?

extensive storage occurs within the colloid of thyroid follicles as part of the glycoprotein, thyroglobulin

How are thyroid hormones released?

the lipophilic structure of these hormones allows for simple diffusion across cell membranes

How are protein/peptide hormones transported?

• transported

  -readily dissolve in plasma (commonly circulate in their free, unbound form); Why?

  -hydrophillic

• Degraded

  -intracellular inactivation: via endocytosis of hormone-receptor complexes & subsequent lysosomal degradation

  -AND extracellular inactivation: AAs are cleaved by peptidases associated with cell membranes or the ECF

How are protein/peptide hormone ultimately eliminated from the body?

eventually excreted via the urine (small peptides can be excreted in their active form without any degradation)

What is the half-life of peptide/protein hormones?

-relatively short half-life (range ~ 2-60 minutes); how can half-life be increased?

  -↑ peptide length, disulfide bonds, glycosylation, sulfation, & acetylation all can ↑ half-life

How are catecholamines transported?

-transported

  -these are hydrophilic molecules that readily dissolve in plasma

  -can circulate in their free, unbound form or loosely bound to albumin

How are catecholamines degraded and excreted?

• intracellular inactivation: via endocytosis of hormone-receptor complexes & subsequent lysosomal degradation

  -inactivated forms are able to diffuse out of cells

• excreted via the urine

What is the half-life of catecholamines?

short half-lives (only a few minutes) 

How are steroid and thyroid hormones transported?

• lipophilic molecules with limited solubility in plasma

  -most circulate bound to plasma proteins, which ↑ solubility

  -as the amount of free hormone in plasma is depleted, bound hormone will dissociate from binding proteins

What proteins bind and transport steroid and thyroid hormones in the blood?

• albumin (general binding proteins)

  • have a low binding affinity for specific hormones but there is a high concentration present in the plasma

  • therefore, albumins have a high capacity for hormone transport

• steroid-specific binding proteins

  • e.g. transcortin has a high affinity for cortisol & corticosterone

• thyroid hormone-specific binding protein

  • thyroid hormone-binding globulin

What is the half-life of steroid & thyroid hormones?

protein-bound steroid & thyroid hormones have a prolonged half-life (hours to days)

How are steroid hormones inactivated and eliminated?

• conjugated with sulfates or glucuronides in the liver; why?

  • this inactivates hormones & ↑ their solubility in H₂O

    • this alteration allows for the excretion of inactivated hormones via the urine

  • some glucoronidated steroids are secreted from the liver with bile

    • allows for excretion via the feces

How are thyroid hormones degraded and eliminated?

• thyroid hormones are deiodinated in many bodily tissues

  • an important mechanism to inactivate thyroid hormones

• thyroid hormones are also conjugated with sulfates or glucoronides in the liver

  • allows for excretion via the feces, as well as the urine (see above)

 

Therapeutic Hormone Administration: Protein & peptide hormones

• these hormones are readily digested & thus, inactivated in the GI tract

• therefore, administration is limited to the parenteral routes (e.g. IV, IM, SQ)

• small peptides can also be formulated for transmucosal administration (e.g. sublingual, intranasal)

Therapeutic Hormone Administration: Thyroid hormones

• oral & parenteral administration (readily absorbed from the GIT in their active form)

Therapeutic Hormone Administration Catecholamines

• oral, parenteral, & inhaled (transmucosal)

Therapeutic Hormone Administration: Steroid hormones

• oral, parenteral, inhaled (transmucosal) & transdermal

When measuring hormone concentrations Which hormone structures should be (or are being) evaluated?

prohormone vs. active hormone vs. hormone metabolites

• some prohormones are released in blood & some are released at higher concentrations than the active hormone (e.g. T₄)

  • metabolites often measured in fecal or urine samples

  • free, unbound hormone vs. hormone bound to binding protein

• availability of binding proteins can influence the concentration of bound hormones

  • need to consider: is a hormone primarily bound or unbound in circulation?

Which classes of hormones utilize plasma membrane receptors?

utilized by hydrophilic hormones (peptides, proteins, catecholamines)

Which classes of hormones utilize cytoplasmic/nuclear receptors?

• utilized by lipophilic hormones (steroids, thyroid hormones)

Why can very low concentrations of a hormone produce a significant target-cell response?

• hormone receptors have a high affinity for their specific hormone(s)

  • this allows small plasma hormone concentrations to elicit significant tissue responses

  • as affinity ↑, so does the duration of the cellular response

which cellular response is more rapid, membrane receptor signaling or nuclear receptor signaling?

membrane receptor signaling

In what state must steroid and thyroid hormones be in to cross cell membrane and bind receptor?

hormones must be in free, unbound form

What is required for a hormone’s action to be terminated?

1) ↓ in the plasma hormone concentration

  -hormones exist in equilibrium between the bound & unbound state (bound to binding protein or receptor)

  -a ↓ in the amount of unbound circulating hormone → a ↓ in the amount of hormone bound to its receptor

 2) and/or endocytosis of the receptor-hormone complex

  -allows the target cell to terminate the signal

    -the internalized hormone is degraded by lysosomal enzymes

  -the internalized receptor can be recycled back to the plasma membrane

 

Upregulation of receptors

• due to ↑ receptor synthesis or ↑ receptor recycling

• often occurs when a hormone’s concentration is pathologically reduced

• helps promote a cell’s response to minimal hormonal stimulation

Downregulation of receptors

• due to ↓ receptor synthesis or ↑ receptor degradation

• often occurs when a hormone’s concentration is pathologically elevated

• helps to limit a cell’s response to continued stimulation

hypersensitization

↑ binding affinity of the receptor for the ligand

desensitization

↓ binding affinity of the receptor for the ligand

What determines the plasma hormone concentration…production or elimination?

• (a hormone’s effects are proportional to the plasma hormone concentration)

• the rate of hormone inactivation is relatively constant

• therefore, the rate of hormone synthesis/secretion primarily determines the plasma hormone concentration

Negative feedback loops

• continuously regulate hormone secretion in an attempt to maintain homeostasis

  • elevated target organ hormone concentrations → negative feedback loops inhibit hormone secretion

  • reduced target organ hormone concentrations → reduced inhibition mediated by negative feedback loops

What is a long feedback loop?

-target organ hormone-mediated inhibition of hypothalamic & anterior pituitary hormones

  -e.g. thyroid hormone inhibition of TRH & TSH release

  -this is the most well-understood loop

what is a short feedback loop?

• pituitary hormone-mediated inhibition of hypothalamic releasing hormones

  -e.g. TSH inhibition of TRH (not shown)

How do positive feedback loops differ?

-much less common than negative feedback loops

  -not involved in maintaining homeostasis; instead, the goal is a specific endpoint (e.g. parturition)

Accuracy

the extent to which a measurement is close to the true value

Precision

the extent to which a measurement procedure gives the same result each time it is repeated under    identical conditions

Sensitivity

-smallest concentration of a substance that can be reliably measured by a given analytical method

  -poor sensitivity can result in: false negative test results

Specificity

-the ability of an analytical method to only identify a certain substance

  -poor specificity can result in: false positive test results

What organ is considered the “master regulator” of the endocrine system? Why?

-hypothalamus

  -links the nervous and endocrine systems, converting information into coordinated hormonal responses

How is the hypothalamus connected to the pituitary?

Pituitary stalk

What does the pituitary stalk contain?

• blood vessels

• axons of neurons

What are the two regions of the pituitary?

Adenohypophysis = anterior lobe of pituitary

-vascular connections with the hypothalamus

Neurohypophysis = posterior lobe of pituitary

  -neural connections with the hypothalamus

What type of cells are present in Adenohypophysis = anterior lobe of pituitary?

consists of endocrine cells (adeno = gland)

What type of cells are present Neurohypophysis = posterior lobe of pituitary?

consists of neurons

What specialized vascular structure connects the hypothalamus and the anterior pituitary?

Portal system of the pituitary gland

  -a portal system is a specialized arrangement of blood vessels

• typical arrangement:

   arteries → arterioles → capillaries → venules → veins

• portal system:

  arteries → arterioles → capillaries → venules/veins → capillaries → venules → veins

What is the physiological benefit of this portal system?

• hypothalamic hormones do not have to travel through the general circulation to reach their target cells in the anterior pituitary

• this is functionally important because all hypothalamic regulatory hormones are short peptide hormones with very short half-lives

What controls secretion of hypothalamic hormones?

Neural signals and hormones

Are hypothalamic hormones stimulatory or inhibitory?

both

What controls secretion of anterior pituitary hormones?

Hypothalamic regulatory hormones

Are hormones from the anterior pituitary stimulatory or inhibitory?

-Stimulatory

What 6 major hormones are made by the hypothalamus?

•GnRH

•CRH

•TRH

•Dopamine

•GHRH

•Somatostatin

What about “PRH”?

•A specific PRH and associated receptor have not been identified

•TRH and some GI hormones can stimulate PRL but not with the same direct regulatory relationship as classical hypothalamic releasing hormones

Which hypothalamic hormones are stimulatory?

•GnRH, CRH, TRH, GHRH

Which hypothalamic hormones are inhibitory?

•Dopamine, Somatostatin

Which hormones are made by anterior pituitary?

• ACTH

• FSH

• LH

• TSH

• GH

• PRL

What cell type makes each hormone?

• Corticotrophs (ACTH)

• Gonadotrophs (FSH)

• Gonadotrophs (LH)

• Thyrotophs (TSH)

• Somatotrophs (GH)

• Lactotrophs (PRL)

CRH is secreted in a….

diurnal (daily) secretion pattern

  -peak secretion occurs in the early AM; trough secretion occurs late in the afternoon

CRH binds to which receptor in which organ?

• corticotropin-releasing hormone receptor (CRH-R1) in anterior pituitary gland

CRH-R1 is expressed on which cell type of the anterior pituitary gland?

corticotrophs

CRH-R1 is what kind of receptor? How does its activation affect target cells?

Gs-linked GPCR that stimulates both POMC transcription & release

What enzyme cleaves POMC into several bioactive peptides?  

prohormone convertases

What are the products of POMC cleavage?

corticotropin (ACTH), lipotropins, melanocyte-stimulating hormones, & endorphins

• corticotropin (ACTH) is the only one with significant physiologic activity in domestic mammals

ACTH is secreted in a….

-diurnal (daily) secretion pattern

  -peak secretion occurs in the early AM; trough secretion occurs late in the afternoon

How is ACTH transported in circulation?

-~ 50% is free & 50% is protein-bound

  -specific binding protein = corticotropin-binding globulin

  -binding not required for solubility but extends half-life to make to target organ

What is ACTH half-life?  

short half-life (10 minutes)

To what receptor does ACTH bind? Where?

melanocortin-2 receptor (MC2R) expressed on adrenal cortical cells