Endocrine Exam 1 Dr.A

hormone definition

biochemical substances released to interstital fluid to regulate cell's biological activity

what is an axis

a series of linked hormonal responses that cause change in the synthesis of other hormones

how are peptide hormones synthesized

they're gene encoded and are produced through transcription and translation

how are steroid hormones synthesized

steroid hormones are produced enzymatically

but you still need to production of enzyme proteins

storage of peptide vs steroid hormones

peptide- secretory granules accumulate pro-hormones

steroids- little/no storage but can store cholesterol precursor

solubility of peptide vs steroid hormones

peptides are soluble in water

steroids are soluble in lipids

transport of peptide vs steroid hormones

peptides are soluble and travel through plasma

steroids need carrie proteins in the plasma and cytoplasm

what are the 3 types of signaling regulation

1. autocrine

2. paracine

3. endorine

autocrine regulation

cells producing hormone respond to that same hormone

paracrine regulation

cells near producer cell respond to hormone (don't travel a long distance)

endocrine regulation

hormone travels (via blood) to distant responder

endocrine vs nervous signaling- response time

endocrine has a slower response time

have to synthesize hormone and transport it through blood

endocrine vs nervous signaling- nature of response

endocrine has synthetic reactions (new mRNAs & new proteins)

nervous signaling is membrane depolarization or contraction

endocrine vs nervous signaling- duration

endocrine duration is longer

endocrine vs nervous signaling- transport route

endocrine: blood stream

nervous: axon + synapse

length of peptide hormone structure

can be very diverse in length- a few amino acids to 100+ amino acids

what is unqiue about the amino acid structure of peptide hormones?

there is no iniator methionine/AUG codon

proteolytic processing of peptide hormones

some peptide hormones are produced by cleaving precursor proteins

for example, POMC becomes ACTH and MSH

if there is not enough ACTH, what happens to MSH as a result

increase in MSH because there will be more POMC cleaving

steroid hormone structure

complex carbon ring structure derived from cholesterol

how is information communicated from a hormone

peptide hormone can bind on the extracellular domain receptor and transfer the information across the membrane (hormone entry into the cell isn't absolutely required)

what are the 2 ways that enzyme activation can occur when a hormone binds to its receptor

receptor with activity

or

receptor associated with proteins with enzyme activity

what is the general effect of hormone binding to extracellular receptors

cascade event where one binding triggers repeated enzyme activity

GPCR + peptide hormone effect

induces dissociation of trimeric G protein

signal is transfered and activates enzyme with production of cAMP (2nd messenger)

receptor tyrosine kinase + peptide hormone effect

tyrosine kinase activity can be as aprt of the receptor or a protein associated with the receptor

the hormone binds which casues receptor dimerization --> kinase activation

autophosphorylation or phosphorylation of another kinase

what are the 2 types of intracellular receptors

cytoplasmic or nuclear

2 domains of intracellular receptors

hormone binding domain and DNA binding domain

what happens when the hormone binds to the hormon-binding domain of intracellular receptors

-hormone causes receptor conformation change -> releases HSP (heat shock protein)

-receptor and hormone translocate to nucleus and activate transcription

role of DNA binding domain of intracellular receptors

allow receptor & hormone to bind DNA for transcription

where is the receptor for steroids & liophilic hormones usually found

in the cytoplasm complexed with HSP

HPA axis- anterior pituitary path

releasing/inhibiting hormone from the hypothalamus regulate production of "tropic" hormone in the AP

HPA axis- posterior pituitary path

hormone production occurs in the hypothalamus but is released from PP

another name for pituitary

hypophysis

another name for the anterior pituitary

adenohypophysis

tropic hormone

causes production of effector hormone in target endocrine glands (i.e. adrenal)

how is the anterior pituitary formed?

embryonic origin from the Rathke's pouch

tubular invagination of pharyngeal epithelium

arises independent of the hypothalamus

how is the aneterior pituitary connected to the hypothalamus

via the portal system

another name for posterior pituitary

neurohypophysis

origin of posterior pituitary

comes from embryonic brain and is an ouotgrowth of the hypothalamus

retains axonal tracts coming from the hypothalamus

how is the posterior pituitary connected to the hypothalamus

physically connected

hormones directly delivered here

have neurons/nuclei that travel between them

what cells produce ADH in the PP

supraoptic nuclei

what cells produce oxytocin in the PP

paraventricular nuceli

how are hormones made and then sent to the posterior pituitary from the hypothalamus

1. synthesis in neuron cell body on eER

2. packaged into secretory grancules

3. transported along axon

4. released onto surface of posterior pituitary

median eminance

multiple hormones are made here for delivery to the anterior pituitary

how are hormones made and then sent to the anterior pituitary from the hypothalamus

1. made in the median eminence

2. travel through the hypothalamic-hypophysial portal system

3. arrive at anterior pituitary

4. AP responds with production & release of tropic hormones

what controls how much hormone is produced from the anterior pituitary

the hormone produced from the hypothalamus that travels to the AP

signaling requirement for the hypothalamic-hypophysial portal system

hormones must be able to cross the BBB which is formed by cell-cell junctions

what is the portal system

blood vessel cells with fewer tight junction which allows for more movement across the vessel wall

(think hypothal--> AP)

unique arrangement of blood vessels in the hypothalamic hypophysial portal system

1. capillaries (hypothalamus)

2. veins (connecting stalk)

3. capillaries (anterior pit)

which 2 hormones are hypothalamus-posterior pituitary hormones

ADH (vasopressin) and oxytocin

which hormones are hypothalamus- anterior pituitary hormones

GnRH --> FSH + LH

what are the 3 diagnostic hormones and where are they made

-GHRH

-TRH

-CRH

all made in the hypothalamus and go to the AP

potential problems with the clinical use of diagnostic hypothalamic hormones

-isolate, puroify, & stabilize hormones (deliver peptide across BBB is hard)

-delivery of sufficient amount to traget cell

-downstream effector hormone may be more specific (may not be specific dor the hormone you want to target)

what downstream effect does CRH (corticotropin releasing hromone) have?

CRH --> POMC --> ACTH

therapeutic hypothalamic hormones that go to the posterior pituitary

ADH and oxytocin

therapeutic hypothalamic hormones that go to the anterior pituitary

GnRH (or synthetic analogs) and SRIF (somatotropin release- inhibiting factor/ somatostatin)

how is the PP and hypothalamus connected

there is an ANATOMICAL CONNECTION between the 2

synthesis steps of ADH/vasopressin

1. 9aa peptide acts as a signal sequence that directs the protein to the surface of the ER

-made as a precurosr protein in the supraoptic nuclei of the hypothalamus

-precursor transported+ processed along nerve tract to PP

2. signal peptidase cuts the end off

what are the 2 types of ADH receptors, where are they and what do they do?

V1: in blood vessel smooth muscle for contraction

V2: in kidney tubule cells to help with water recovery

how does ADH binding to V2 cause feedback regulation?

increase in BP has negative feedback on ADH production

V2 + ADH binding downstream steps

-they bind and adenyl cyclase is actived

-adenyl cyclase increases phosphate sources

-protein kinase A then uses phophates to phosphorylate proteins in the cell

-phosphorylated proteins change shape and aggregate

-aggregation of proteins water water channels in the kidney cell membrane

-more water is reabsorbed through the lumen and the blood volume increases

-increase in blood volume increases BP

ethanol effect on ADH

inhibits ADH release which causes dehydration/hangover

nicotine, morphine, and barbiturate effect on ADH

increase ADH release

ADH steps with a decrease in osmotic pressure

osmotic pressure is low due to insufficient water intake

§ Sensed by osmoreceptors in the hypothalamus

§ Supraoptic nuclei in hypothalamus releases ADH

§ Increased reabsorption of water in kidney restores osmolality

ADH steps with a decreased blood pressure

§ Sensed by baroreceptors in the heart

§ Signal sent to supraoptic nuclei in hypothalamus

§ Supraoptic nuclei releases ADH

§ Water is reabsorbed which increases blood volume/ BP

clinical application of ADG

diabetes insipidus

o Very low ADH--> high urine output--> high thirst

o Successfully treated if ~20% normal ADH level restored with a synthetic peptide

what is oxytocin and what does it do?

it is a small peptide hormone

has the ability to increase uterine muscle contraction (bind to smooth muscle in uterus)

oxytocin in pregnancy

-induces labor late in pregnancy by increasing receptors on uterine smooth muscle

-contraction of breast myoepithelial cells to promote milk secretion

how is oxytocin peripherally produced?

produced late in pregnancy by the placenta

local concentration in uterus>>> maternal circulating hormones

how is oxytocin produced in the brain?

it is synthesized by the hypothalamus' paraventricular nuclei

which route of administration can not be used with oxytocin

it is a peptide so not PO

MOA of oxytocin in clinical uses

can be used for contraction in labor and delivery

it is being investigated for its neuromodulation effects in autism therapy

what does GnRH stand for?

gonadotropin releasing hormone

how is GnRH made in the body

made in the hypothalamus from a pre-prohormone precursor

where does GnRH have an effect?

stimulates the GnRH receptor on gonadotrope cells in the anterior pituitary

downstream effect of GnRH

binds to receptor inAP

activates the 2nd messenger system

LH + FSH (gonadotrope hormones) are produced

what does the amount of LH or FSH depend on?

the frequency and level of GnRH

what is the pattern of GnRH release like?

its release is pulsatile which means it causes oscillating levels in hormonal delivery (15 mins per 90 mins)

amplitude + frequency increase with puberty

how does receptor attenuation occur?

GnRH receptors become desensitizes when there are constant high levels of GnRH instead of the normal pulsatile release

what is the effect of GnRH receptor attenuation?

receptor activity becomes down-regulated

cells dependent on testosterone and estrogen for mitotic stimulus are then decreased

when is continuous high therapeutic levels of GnRH advantageous?

o Advantage if desired effect is to decrease secretion of FSH and LH

§ Treat with synthetic agonist with a longer half life

§ Eventually causes attenuation of GnRH receptor on membrane on ant pit cells

§ Attenuation is not immediate - may need several days of high GnRH therapy

what are the initial consequences of high GnRH treatment (trying to achieve receptor attenuation)?

initially causes rapid cell growth before attenuation occurs then cells decrease once the receptor is desensitized

how can GnRH be used for amenorrhea?

GnRH can be used to increase gonadotrope hormones (FSH and LH)

causes induction of ovulatiion

**only if pituitary has normal function and the ovary is responsive

how is GnRH administered for amenorrhea?

pulsed IV delivery

cannot be given at a constant high because this will cause receptor attenuation

how do we treat gonadotrope-dependent cancers with GnRH?

through "pharmacological castration" where GnRH receptors are attenuated so they produce less gonadotrooins

how do we treat emdometriosis with GnRH?

we can attentuate receptors to decrease the amount of gonadotropin released

decreases the size and pain associated with excess cell grwoth

leuprolide

GnRH peptide agonist analog used to cause attenuation and decrease FSH/LH secretion

how is leuprolide structurally different from GnRH

has a D-Leu instead of L-Leu

Conformation change makes it less recognizable by breakdown enzymes

function of female FSH

ovarian follicle growth & synthesis of estrogen

function of male FSH

sperm development by supporting Sertoli cell function

steroli cell

support cell to HELP stimulate sperm production

function of female LH

ovulation & synthesis of progesterone (& continued estrogen) within corpus luteum

function of male LH

testosterone synthesis in Leydig cells

FSH + LH structure

made of 2 polypeptide chains with same alpha but different beta chains

each chain is modified post-translationally

how are FSH and LH different

they have different beta chains which determines their identity

how are FSH and LH chains modified post-translationally

Added carbohydrate groups that affect hormone solubility, stability & recognition by receptor

where are LH and FSH receptors

on the cell surfaces in the testes and ovaries

describe the structure of FSH and LH receptors

have an exttracellular domain made of beta sheets

7TMR

receptors are specific for FSH or LH

are GPCR coudpled do adenyl cyclase --> cAMP

why are FSH and LH administered via injection?

Difficult to prevent digestive tract breakdown of orally administered peptide/protein compound

what are the 2 ways that AP hormones can be regulated?

via hypothalamic relseasing factors (hormones) OR inhibiting factors (hormones) both from the median eminence (neurosecretory cells in the hypothalamus)