PLN203 - endocrine

endocrine system regulates

• growth

• development

• reporduction

• uses chemical messangers to relay information and instructions between cells

what is the largest endocrine oragin

• GI tract

Hypothalamus hormones

• ADH

• oxytocin

• regulatory hormones

Pituitary gland

• anterior lobe

  • ACTH

  • TSH

  • GH

  • PRL

  • FSH

  • LH

  • MSH

• Posterior lobe

  • Oxytosin and ADH

Penal Gland hormone

• melatonin

  • circadian rhythm

  • inhibiting reproduction

  • free radical protection

Parathyroid glands

• PTH

  • parathyroid hormone

Thyroid hormones

• thyroxine T4

• triodothryonine T3

• Calcitonin

Adrenal Glands

• Adrenal Medulla

  • Epinephrine

  • Norephrine

• Adrenal Cortex

  • cortisol

  • corticosterone

  • aldosterone

  • androgens

Pancreas hormones

• insulin

• Glucagon

Adipose tissue secretes

• leptin

Direct communication

• Exchange of ions and molecules between adjacent cells across gap junctions

  • transport cells required

• Occurs between two cells of the same type

• specialized and rare

• moving to neighbor cells

Paracrine communication

• uses chemical signals to transfer information from cell to cell within a single tissue

• most common form of intercellular communication

Endocrine communication

• endocrine cells release chemicals (hormones) into the bloodstream

• alteration of metabolic activities in many tissues and organs simultaneously

Target cells

• specific cells that possess receptors that are needed to bind and read hormonal messages

  • where hromones are aiming to act

Hormones

• stimulate synthesis of enzymes or structural proteins

• increase or decrease the rate of synthesis

• turn existing enzyme or membrane channel on or off

  • can act to stimulate a cascade within a cell to change protein synthesis in a cell

Synaptic communication

• occurs across synaptic clefts

• chemical message is neurotransmitter

• limited to specific area

Classes of hroomones

• AA derivatives

• peptide derivatives

  • AA chains in fragments

• lipid derivatives

  • has lipid components

distribution of hormones

• can circulate freely or travel bound to special carrier proteins

AA derivitives

• molecules structurally related to AAs

• derivatives of tyrosine

  • Thyroid hormones

  • catecholamines

    • epi, norepi, dopamine

• derivatices of tryptophan

  • serotonin and melatonin

Peptide hormones

• AA chains

• synthesized as prohormones

  • inactive molecules converted to active hormones before or after they are secreted

• Glycoproteins

  • Proteins that are more than 200AA long and have carbohydrate side chains

    • TSH, LH, FSH

• Short polypeptides/small proteins

  • all proteins secreted by hypo, heart, thalamus, pancreas, posterior pitutary

    • Short chain polypeptides

      • ADH (oxytocin and vasopressin)

    • small proteins

      • GH and prolactin

Glycoproteins

• 200+ AA long which have carbohydrate side chains

• Thyroid stimulating hormone

• leutinizing hormones

• follicle stimulating hormone

Short chain polypeptides

• only 9 AAs

• ADH

  • Vasopressin and oxytocin

    • acts on nephron for the regulation of kidney fluid balance

  • reduces how often you have to pee

Small proteins

• 200 AAs ish

• GH and prolactin

Lipid derivitives

• Eicosanoids - 20 carbon fatty acid

• Steroid hormones

  • derived from cholesterol

Eicosanoids

• 20 carbon Fatty acid

• paracrine factors coordinate cellular activities and effect enzymatic processes in extracellular fluids

• some have secondary roles as hormones

• Second group is Prostaglandins

  • coordination of local cellular activities

  • converted to thromboxjnes and prostacyclins which have paracrine effects

Prostoglandins

• second group of Eicosanoids

• primarily involved in coordination of local cellular activities

• in some tissues these are converted to thromboanes and prostacyclins which have pancrean effects

Leukotrienes

• eicosanoids with a secondary role as hormones

Steroid hormones

• cholesterol derivatives

• released by

  • reproductive organs (androgens, estrogens, progestines)

  • cortex of adrenal gland (corticosteroids)

  • kidneys (calcitriol)

• bound to transport proteins in the plasma so they are able to remain in circulation longer than free hormones

Free Hormones

• remain functional less than an hour

• diffuse out of bloodstream and bind to receptors on target cells

• broken down and absorbed by cells in the liver and kidneys

• broken down by enzymes in the plasma or intersitial fluids

Distribution of thryoid and steroid hormones

• remain in circulation longer because they are bound

• enter the bloodstream

  • 99% will attach to special transport proteins

  • Albumin binds these hormones

Albumin

• hormone binding agent that transports hormones through the blood

Hormone receptor

• the part of a protein molecule that binds strongly to a molecule

• responds to several different hormones which are similar in shape and side

  • this is why supplements work by mimicking hormones to bind receptors and trigger the cascades

• the presence or absense of these is what determines hormone sensitivity

Up and downregulation of receptor numbers

• when there is too much of a hormone there will be less receptors making the cell less sensitive to the hormone

• when there is too little there will be an increase in the number of receptors making the cell more sensitive to the small amount of the hormone

Leptin and up and down regulation

• the issue isnt that there is a deficiency in leptin it is that cells have downregulated the receptors that are meant to trigger a response to leptin meaning that cells are less responsive to the present leptin

Catecholamines and peptide hormones (receptors)

• not lipid soluble

• unable to penetrate plasma membrane

• must bind to an extracellular receptor to trigger a cascade that can change transcription and translation

Eicosanoids and plasma membrane receptors

• lipid soluble

• diffuse readily across the plasma membrane to each receptor proteins that are on the innner surface of plasma membrane (intracellular receptors)

First and second messangers

• bind to receptors in the plasma membrane

• cannot have direct effects on the activities inside the target cell

• intracellular intermediary to exert effects on the cell

First messanger

• leads to a second

• can act as an enzyme activator, inhibitor, or cofactor

  • may or may not want the doors to be open

  • - feedback with multiple doors to open and close

• results in change in rates of metabolic reactions

Main second messangers

• Cyclic-AMP (cAMP)

  • Adenosine mono phosphate

    • ATP derivitive

• Cyclic-GMP (cGMP)

  • GTP derivative

• Calcium Ions

  • Ca++

Amplification process

• binding of a hormone to a receptor

• triggers a cascade throughout the cell by releasing thousands of second messangers in the cll

• magnifies the effect of the hormone on the target cell

DOWN regulation of hormone receptors

• presence of a hormone triggers a decrease in the number of hormone receptors

• when levels of a hormone are high the cells become less sensitive to them

UP regulation of hormone receptors

• absence of hormone triggers an increase in the number of hormone receptors

• when levels of particular hormones are low, cells become more sensitive to them

What substance activates protein kinases and thus acts as a secondary messanger?

A. insulin

B. ACTH

C. Epinephrine

D. c-AMP

E. two of the above

G-protein

• enzyme complex that is linked to a membrane receptor

• involved in the link between the first and second messengers

G proteins and cAMP

• adenylate cyclase is activated when a hormone binds a receptor at the membrane surface and creates a change in the concentration of second mesanger cAMP in the cell

  • this increases the metabolic activity within a cell

Adenylate cyclase

• is activate when the g-protein is activated through the binding of a hormone

• it is responsible for converting ATP into cAMP (second messenger)

• this allows the opening of ion channels and the activation of enzymes and metabolic activity within the cell

What hormones can bind to produce cAMP

• Epinephrine and norephrine if they bind to a beta receptor

• calcitonin

• PTH

• ADH, ACTH, FSH, LH, TSH

• glucagon

Hormones binding to lower cAMP

• bind to gprotein

• cAMP is broken down by PDE creating AMP

  • this reduces enzyme activity within the cell

  • inhibitory effect

• Epinephrine or norephrine if it acts on alpha cells

G-proteins and calcium ions downstream events

• Activated g proteins trigger the openign of Ca++ ion channels in the membrane

• releases calcium ions fron intracellular stores

• activates PLC (phospholipase C)

• triggers receptor cascade

  • DAG and IP3 are created from membrane phospholipids

  • may further activate more calcium ion channels through PKC

  • may activate calmodulin creating further changes in the cell

What happens when adenylate cyclase is acivated?

• ATP is consumed

• cAMP if formed

Hormones and intracellular receptors

• alter the rate of DNA transcription in the nucleus

• changing the patterns of protein synthesis

• directly affects the metabolic activity and structure of the target cell

• includes steroids and thyroid hormones

Steps of intracellular hormone binding

• Diffusion through membrane lipids

  • lipid soluble so can diffuse through

• binding of a hormone to a cytoplasmic or nuclear receptor

• hormone receptor complex binds to DNA

• gene activation

• transcription of mRNA product

• translation and protein synthesis

• alteration of cellular structure or activity on target cell

Second option for intracellular hormone binding

• hormone receptor complex must bind both a nucleus receptor and one at the mitochondria

  • the nucleus will continue in to bind DNA, alter transcription of mRNA, synthesis proteins and alter the structure of activity

• the mitochondria hormone receptor complex will increase the production of ATP which is required to power the target cell responses by providing cell energy

3 mechanisms for hypothalamic control over endocrine function

• production of ADH and oxytosin

  • hypothalamus acts directly onto the posterior lobe of the pituirary gland

• Secretion of regulatory hormones to control the activity of the anterior lobe of the pituitary gland

  • hormones secreted by anterior lobe controle other endocrine organs

• control of the sympathetic output to adrenal medullae

  • secretion of epinephrine and norephtine

Neuroendocrine reflexes

• pathways including both neural and endocrine components

• commands issued by changing

  • amount of hormone secreted

  • pattern of hormone release

    • hypothalamic and pituitary hormones released in sudden bursts

    • frequency changes the response of target cells

Pituitary gland location and structure

• aka hypophysis

• dural sheet locks it into position

• isolates it from the cranial cavity

• hangs inferior to hypothalamus

  • connected by the infundibilum

Pituitary gland hormones

• releases 9 important peptide hormones

• hormones bind to membrane receptors

• use cAMP as a second messanger

what are the subsets of the anterior lobe

• pars tuberalis

• pars distalis

  • other put hormones

• pars intermedia

  • secretes MSH

Anterior lobe of the pituitary

• aka adenohypophysis

  • hormones turn on endocrine glands or support other organs

• split into 3 regions

  • pars distalis

  • pars tuberalis

  • pars intermedia

Hypophyseal portal system

• median eminence

  • swelling near attachment of the infundibulum

  • where hypothalamic neurons release regulatory factors

    • go into intersital fluids through fenestrated capillaries

      • window into capillaries of the portal system in pituitary

Portal Vessels

• BV link two capillary networks

• whole complex is a portal system

  • ensures that regulatory factors reach their target cells before entering the general circulation

two classes of hypothalamic regulatory hormones (acting on anterior lobe)

• RH

  • stimulate the synthesis and secretion of one or more hormones at the anterior lobe

• IH

  • prevents the synthesis and secretion of hormones from the anterior lobe

• Rate of secretion is controlled by negative feedback

Feedback control of the endocrine system

• RH from hypothalamus goes to anterior lobe → releases hormone 1 → acts on endocrine organ → releases hormone 2 → acts on target cells

  • Hormoen 2 will also loop back up to the anterior lobe and the hypothalamus to prevent the syntehesis of more hormone 1

    • blocking its own production

    • when it reaches a certain concentration it wants the RH to not over produce

Examples of endocrine feedback

• TRH (RH) → TSH (hormone 1 from pituitary) → thyroid gland (endocrine target organ) → thyroid hormones (hormone 2 from target organ)

• CRH (RH) → ACTH (Hormone 1 from pituitary) → adrenal cortex (target organ) → glucocorticoids (hormone 2 from target organ)

Feedback of endocrine system with releasing and inhibition hormones from hypothalamus

• GH-RH (hypo) → anterior lobe → GH → Liver → Somatomedins → growth of muscle and other tissues

• GH-IH blocks the production of GH from the anterior lobe

If the median eminence of the hypo was destroyed the hypo could no longer control the secretion of

• TSH, ACTH, P…

Posterior lobe

• neurohypophysis

• containes unmyelinated axons of th ehypothalamic neurons

• supraoptic and paraventricular neuclei manufactor

  • ADH (Acts on kidneys)

  • OXT (acts on smooth muscle in males and uterine smooth muscles in females)

Change in blood osmotic pressure would more affect the secretion of

• ADH

  • want to produce more ADH to stop the body from urinateng as much (water retention)

thyroid gland

• lies anterior to the thyroid cartilage of the larnyx

• consists of two lobes connectd by narrow isthmus

  • thyroid follucles

    • hollow spheres lined by cuboidal epothelium

    • cells surround follicle cavity that contains viscous colloid

    • surrounded by capillaries that deliver nutrients and regulatory hormones and accept secretory produces and metabolic wastes

Thyroglobulin

• globular protein made by the thyroid

• synthesized by follicle cells

• secreted into colloid of thyroid follucles

• molecules contain amino acid tyrosine

Thryoxine

• T4

• Tetraiodothyronine

• contains 4 iodine ions

Triiodothronine

• T3

• contains 3 iodine ions

Where does the chemical reaction between thyroglobulin and iodine take place

• in the lumen of the thryoid follicle

Production of thyrpod hormones

• diffuseion of iodine through a TSH sensitive ion pump

• Iodine diffuses through to the apical surface of the folicle cell

• tyrosine portion of thyroglobin binds the iodine atoms

• iodine containing thyrosine molecules links to form T3 and T4

• follucle cells move the thyroglobin from the follicles by endocytosis

• lysosome cells break down thryoglobulin and the AA and thyroid hormones enter the cytoplasm

• released t3 and t 4 diffuse from follicle cell into bloodstream and bind transport proteins

Regulation of thyroid secretion

• Homeostasis = normal T3 and T4 concentrations, normal body temp

• Homeostasis disturbed (lower T3 and T4 in blood or low body temperature)

• hypo releases TRH to act on the anterior lobe

• Anterior releases TSH to act on thyroid gland to release T3 and T4

• homeostasis restored

TBG (Thyroid binding globulins)

• plasma proteins that bind abotu 75% of T4 and 70% of T3 entering the bloodstream

Transthyretin (thryoid binding prealbumin-TBPA) and albumin

• binds the remaining thyroid hormones

• 0.3% of T3 and 0.03% of T4 are unbound

TSH

• absence causes thyroid follicles to becone inactive

  • neither synthesis or secretion occurs

• binds membrane receptors

• activates key enzymes in thyroid hormone production

Marty feldman

• graves disease

• effects the thyroid gland

Functions of thyroid hormones

• enters target cells by transport system

• affect most cells in body

• bind to receptors in:

  • cytoplasm

  • surfaces of mitochondria

  • nucleus

• In children essential to normal development of

  • skeletal, muscular and nervous system

Calorigenic effect

• cell consumes more energy resultin in increased heat generations

  • cell consumes too much energy

• Responsible for strong, immediate and short lived increase in rate of cellular metabolism

  • dysfunction of thyroid can mess with body fitness

Effects of thyroid hormones

• elevates rates of oxxygen consumption and energy consumption - raises body temperature

• increases heart rate and force of contraction; generally results in rise in blood pressure

• increases sensitivity to sympathetic stimulation

• maintains normal sensitivity of respiratory centers to changes in oxygen and CO2 concentrations

• stimulates RBC formation and thus enhances oxygen delivery

• stimulates activity in other endocrine tissues

• accelerates turnover of minerals in bone

Thyroid C cells and calcitonin

• c (clear) cells aka parafollicular cells

• produce calcitonin (CT)

• helps regulate concentrations of Ca++ in body fluids

  • inhibits osteoclasts which slows the rate of Ca++ release from bone

  • stimulates Ca++ excretion by the kidneys

Thyroid hormone action involves all steps except

A. binding to hormone receptor in plasma membrane

B. specific transport into target cell (can diffuse)

C. binding to a cytoplasmic receptor protein

D. activation of specific gene

E. avation of mitochondria

Goitrogens

• compound metabolized to thicyanate and blocks thyrodial uptake of iodine

• some species of millet and cruciferous vegetables also contain goitrogens

  • soybean isoflavones may inhibit thyroid hormone synthesis

• most goitrogens are not of clinical importance unless they are consumed in large amounts and there is a coexisting iodine deficiency

Iodine functions

• essential for T3 and T4

• T4 is abundant in blood

• T3 is the active form of hormone

• conversion of T4 to T3 requires selenium

Thyroid function wihtout sufficient dietary iodine

• there is no negative feedback from T3 and T4 resulting in excess TSH being released into the thyroid and creating a goiter

cretenism

• hyperthyroidism

Parathyroid glands

• 4 glands

• embedded in the posterior surface of the thyroid gland

• only 1.6g

• PTH is produced

  • produced by parathyroid cells in response to low Ca++ concentrations

  • calcitonin antagonist

• wants to release more Ca++ from blood

PTH

• produced in parathyroid chief cells

• responds to low Ca++ in blood

  • takes Ca++ from the bones

  • acts on the nephron distal conv tube to enhance Ca++ reabsorption to reduce the urinary losses

Effects of PTH

• stimulates the osteoclasts and inhibits osteoblasts

  • higher turnover of minerals and more release of Ca++ from bone

  • reduction in the rate of calcium deposition in the bone

• Enhances reabsorption of Ca++ at the kidneys reducing the urinary losses

  • distal convoluted tubule

• stimulating formation and secretion of calcitriol by the kidneys

  • effects complement or enhance PTH

  • also enhances Ca++, PO4- - - absorption by the digestive tract

Regulation of rising levels of blood calcium

• thyroid produces calcitonin → increases the excretion of calcium by the kidneys and deposition of calcium into the bones → homeostasis restored and the calcium levels decline

Regulation of declining Calcium ion levels in blood

• Parathyroid produces PTH → acts to activate osteoclasts and limit osteoblast usage + also increases the reabsorption of Ca from the kidneys + increased calcitriol production causes Ca reabsorption by digestive system → blood homeostasis is restored

• Normal levels 8.5-11 mg/dL

Follicular epithelium

• produces T3 and T4

• targets most cells

• for energy utilization, o2 consumption, growth and development

• stimlated by TSH from the anterior lobe of pituitary

C cells

• Calcitonin

• bone, kidneys

• decreases Ca++ concentrations in the body fluids

• stimulated by elevated blood Ca++ levels; actions are opposed by PTH

Adrenal Glands

• lie on the superior border of each kidney

• divided into

  • Superficial adrenal cortex

  • inner adrenal medulla

Adrenal cortex

• stores lipids especially cholesterol and fatty acids

• manufactures steroid hormones (corticosteroids)

Inner adrenal medulla

• secretory activities controlled by sympathetic division of ANS

  • fight or flight

• Production of epinephrine and norepinephrine

• metabolic changes which persist for several minutes

Adrenal cortex subregions

• zona glomerulosa

• zona fasciculata

• zona reticularis

Zona glomerulosa (adrenal cortex outer region)

• mineralocorticoids

  • aldosterone