Endocrine system

Dr. Victor J. Samillan

ES and Homeostasis• Homeostasis

Tissues can be targeted by multiple hormones

Hormones can act synergistically, permissively, or antagonistically

Synergistic effects of hormones on blood glucose concentration

Peptide Hormones

Synthesis/transport/half-life

Storage?

Multiple processing patterns for protein hormones

Hormone-Receptor interactions• Definition: a protein that binds a ligand with high

affinity and low capacity. This binding must be saturuable.

• A tissue becomes a target for a hormone by expressing a specific receptor for it. Hormones circulate in the blood stream but only cells with receptors for it are targets for its action.

Agonist vs. Antagonist• Agonists are molecules that bind the receptor

and induce all the post-receptor events that lead to a biologic effect. In other words, they act like the "normal" hormone, although perhaps more or less potently

• Antagonists are molecules that bind the receptor and block binding of the agonist, but fail to trigger intracellular signaling events

Metabolic clearance rate (MCR)

• Defines the quantitative removal of hormone from plasma

• The bulk of hormone is cleared by liver and kidneys • Only a small fraction is removed by target tissue

• protein and amine hormones bind to receptors and are internalized and degraded

• Steroid and thyroid hormones are degraded after hormone-receptor complex binds to nuclear chromatin

• 99% of excreted hormone is degraded or conjugated by Phase I and Phase II enzyme systems

MCR of some hormones

Hormone Half-life

Amines 2-3 min

Thyroid hormones: T4 T3

6.7 days0.75 days

Polypeptides 4-40 min

Proteins 15-170 min

Steroids 4-120 min

Methods of intercellular communication by secreted molecules

(a) Endocrine signaling

Bloodvessel Response

Response

Response

Synapse

Response

Response

(b) Paracrine signaling – short distances

(c) Autocrine signaling – short distances

Neuron

(d) Synaptic signaling

Neurosecretorycell

Bloodvessel

(e) Neuroendocrine signaling

Different receptorsSame receptors but differentintracellular proteins (not shown)

Different cellularresponses

Different cellularresponses

Epinephrine Epinephrine Epinephrine

receptor receptor receptor

Glycogendeposits

Vesseldilates.

Vesselconstricts.

Glycogenbreaks downand glucoseis releasedfrom cell.

(a) Liver cell (b) Skeletal muscleblood vessel

Intestinal bloodvessel

(c)

Figure 45.9

Types of receptors

Second messengers for cell-surface receptorsSecond messenger systems include:

Adenylate cyclase which catalyzes the conversion of ATP to cyclic AMP;

Guanylate cyclase which catalyzes the conversion of GMP to cyclic GMP (cyclic AMP and cyclic GMP are known collectively as cyclic nucleotides);

Calcium and calmodulin; phospholipase C which catalyzes phosphoinositide turnover producing inositol phosphates and diacyl glycerol.

Hormones and their receptors

Hormone Class of hormone

Location

Amine (epinephrine)

Water-soluble Cell surface

Amine (thyroid hormone)

Lipid soluble Intracellular

Peptide/protein Water soluble Cell surface

Steroids and Vitamin D

Lipid Soluble Intracellular

Binding vs. biological response

Spare receptors Amplification by 2nd messenger

Spare Receptors• Maximum response with 2-3% receptor

occupancy• 97% of receptors are “spare”• Maximum biological response is achieved when

all of the receptors are occupied on an average of <3% of the time

• The greater the proportion of spare receptors, the more sensitive the target cell to the hormone

• Lower concentration of hormone required to achieve half-maximal response

Spare receptors• In most systems the maximum biological

response is achieved at concentrations of hormone lower than required to occupy all of the receptors on the cell.

• Examples: • insulin stimulates maximum glucose oxidation in

adipocytes with only 2-3% of receptors bound• LH stimulates maximum testosterone production in

Leydig cells when only 1% of receptors are bound

Control Pathways and Feedback Loops

• There are three types of hormonal control pathays

Pathway Example

Stimulus Low bloodglucose

Receptorprotein

Pancreassecretesglucagon ( )

Endocrinecell Blood

vessel

LiverTarget

effectors

Response

Pathway Example

Stimulus Suckling

Sensoryneuron

Hypothalamus/posterior pituitary

Neurosecretorycell

Bloodvessel

Posterior pituitarysecretes oxytocin( )

Targeteffectors

Smooth musclein breast

Response Milk release

Pathway Example

Stimulus Hypothalamicneurohormonereleased inresponse toneural andhormonalsignals

Sensoryneuron

Hypothalamussecretes prolactin-releasinghormone ( )

Neurosecretorycell

Bloodvessel

Anteriorpituitarysecretesprolactin ( )Endocrine

cellBloodvessel

Targeteffectors

Response

Mammary glands

Milk production

(c) Simple neuroendocrine pathway

(b) Simple neurohormone pathway

(a) Simple endocrine pathway

Hypothalamus

Glycogenbreakdown,glucose releaseinto blood

Figure 45.2a–c

Figure 45.8-2

EXTRACELLULARFLUID

Hormone(estradiol)

Estradiol(estrogen)receptor Plasma

membrane

Hormone-receptorcomplex

NUCLEUS

DNA

CYTOPLASM

VitellogeninmRNA

for vitellogenin

Figure 45.7-2

Epinephrine

G proteinAdenylylcyclase

G protein-coupledreceptor

GTP

ATP

cAMP Secondmessenger

Inhibition ofglycogen synthesis

Promotion ofglycogen breakdown

Proteinkinase A

Figure 45.6-2

Lipid-solublehormone

SECRETORYCELL

Water-solublehormone

VIABLOOD

Signal receptor

TARGETCELL OR

Cytoplasmicresponse Gene

regulation

(a) (b)

Cytoplasmicresponse Gene

regulation

Signalreceptor

Transportprotein

NUCLEUS

Lipid-soluble (hydrophobic)Water-soluble (hydrophilic)Polypeptides Steroids

0.8 nmInsulin Cortisol

Amines

Epinephrine Thyroxine

3 Chemical classes of hormones

Because peptides are impermeable, they must use membrane receptors and second messenger signal transduction mechanisms to produce the desired effects.

Most use g-protein coupled receptors, but some use tyrosine kinase type receptors (i.e. insulin)

STIMULUS

HypothalamusReleasing Hormone

(Release-Inhibiting Hormone)

PituitaryStimulating HormoneGland

Hormone Target

Characteristics of hypothalamic releasing hormones

• Secretion in pulses• Act on specific membrane receptors• Transduce signals via second messengers• Stimulate release of stored pituitary hormones• Stimulate synthesis of pituitary hormones• Stimulates hyperplasia and hypertophy of target

cells• Regulates its own receptor

Hypothalamic releasing hormonesHypothalamic releasing hormone Effect on pituitary

Corticotropin releasing hormone (CRH)

Stimulates ACTH secretion

Thyrotropin releasing hormone (TRH)

Stimulates TSH and Prolactin secretion

Growth hormone releasing hormone (GHRH)

Stimulates GH secretion

Somatostatin Inhibits GH (and other hormone) secretion

Gonadotropin releasing hormone (GnRH) a.k.a LHRH

Stimulates LH and FSH secretion

Prolactin releasing hormone (PRH) Stimulates PRL secretion

Prolactin inhibiting hormone (dopamine)

Inhibits PRL secretion

Hypothalamus and Pituitary• The hypothalamus-pituitary unit is the most dominant portion

of the entire endocrine system.• The output of the hypothalamus-pituitary unit regulates the

function of the thyroid, adrenal and reproductive glands and also controls somatic growth, lactation, milk secretion and water metabolism.

Three major groups

1. Posterior pituitary/hypothalamus

• Vasopressin (ADH)

• Oxytocin

2. Anterior pituitary/hypothalamus

3. Catecholamines of the adrenal medulla

Tropic effects only:FSHLHTSHACTH

Nontropic effects only:ProlactinMSH

Nontropic and tropic effects:GH Hypothalamic

releasing andinhibitinghormones

Posteriorpituitary

Neurosecretorycells of thehypothalamus

Portal vessels

Endocrine cellsof the anteriorpituitaryPituitaryhormones

HORMONE FSH and LH TSH ACTH Prolactin MSH GH

TARGET Thyroid MelanocytesTestes orovaries

Adrenalcortex

Mammaryglands

Liver, bones,other tissues

Figure 45.16

Pinealgland

Cerebellum

Spinal cord

Cerebrum

Thalamus

Hypothalamus

Pituitarygland

Posteriorpituitary

Anteriorpituitary

Hypothalamus

Figure 45.14

• The posterior pituitary stores and secretes hormones that are made in the hypothalamus

• The anterior pituitary makes and releases hormones under regulation of the hypothalamus

2. Anterior pituitary –hypothalamus• Prolactin

• Thyroid stimulating hormone (TSH)

• Adrenocorticotropic hormone (ACTH)

• Growth hormone (GH)

• Follicle stimulating hormone (FSH)

• Leutinizing hormone (LH)

Most target other endocrine glands or cells

Example of Hormone Regulation – Vasopressin (ADH)

• Regulation of body water is a response to ECF volume changes (in particular, blood volume)

• When blood volume changes, volume receptors in the blood vessels and atria respond

• Carotid sinus and aortic baroreceptors

• Afferent nerves from these receptors go to the cardiovascular center in the brainstem

• Increased pressure would signal the center to

• Decreased pressure would signal the center to

• When blood volume changes, stretch receptors in the atria also respond

• Increased pressure also signals the cardiovascular center to

• Increased pressure signals the hypothalamus (this is where ADH release is controlled)

• When blood volume increases, filtration in the kidney is adjusted so that more fluid is filtered per minute

• Typically, under normal situations, the kidneys are not under the influence of ADH and water follows ions as they pass through the kidney tubules

• There are few aquaporin molecules in the cell membranes of the kidney collecting ducts in the absence of ADH. They are stored inside the cells.

Influence of ADH on the Collecting Ducts

Feedback Loop for ADH

Negative feedback

What regulates NaCl?

Regulation of Na+• Increasing osmolarity of the blood stimulates thirst behaviors, and increases

ADH secretion. Drinking and preventing water loss from the kidneys, decreases blood osmolarity

How would this graph change if an individual had hypertension (high blood pressure)?

Long-term regulation of Na+ • Under the control of aldosterone; it increases Na+ reabsorption into the

blood from the kidney filtrateWhat will happen to plasma [K+]?

What will be the overall effect on plasma osmolarity?

Oxytocin• Stimulates uterine contractions during childbirth by

mobilizing Ca2+ through a PIP2-Ca2+ second-messenger system

• Also triggers milk ejection (“letdown” reflex) in women producing milk

• Plays a role in sexual arousal and orgasm in males and females