Introduction to Endocrinology

Prof. dr. Zoran Valić

Department of Physiology

University of Split School of Medicine

Coordination of Body Functions

1) nervous system (neurotransmitters into the synaptic junctions – locally)

2) endocrine system (hormones into blood)3) neuroendocrine (neurohormones into

blood)4) paracrines (secreted into extracellular fluid

and affect neighboring different target cells)5) autocrines (affect same cells)6) cytokines (peptides - 5,4 or 2 - interleukins,

lymphokines, adipokines (leptin))

some endocrine hormones affect many different types of cells of the body (growth hormone, thyroxine)

other hormones affect mainly specific target tissues (ACTH – adrenal cortex)

regulation: metabolism, growth and development, water and electrolyte balance, reproduction, and behavior

Chemical Structure and Synthesis

1) proteins and polypeptides

2) steroids

3) derivatives of the amino acid tyrosine (thyroid and the adrenal medullae)

there are no known polysaccharides or nucleic acid hormones

1) Protein Hormones

widespread, water soluble from 3 (TRH) to 200 amino acids (growth

hormone and prolactin) more than100 amino acids – proteins synthesized on the rough end of the ER preprohormones – prohormones (ER) –

hormones (Golgi apparatus & secretory vesicles) – exocytosis (Ca, cAMP)

2) Steroid Hormones

usually synthesized from cholesterol are not stored lipid soluble most of cholesterol comes from plasma, but

there is also de novo synthesis consist of three cyclohexyl rings and one

cyclopentyl ring combined into a single structure

3) Amine Hormones

derived from tyrosine most of the thyroid hormones combine with

plasma proteins 4x more epinephrine than norepinephrine taken up into preformed vesicles and stored

until secreted (exocytosis) in the plasma in free form or in conjugation

with other substances

Hormone Secretion

some hormones (epinephrine) are secreted within seconds after stimulation, and develop action within seconds to minutes

thyroxine or growth hormone may require months for full effect

concentrations of hormones are incredibly small (from 10-12 to 10-6g/ml) – rates of secretion are extremely small (μg-mg/day)

Control of Hormone Secretion

in most instances – negative feedback mechanisms

controlled variable is sometimes not the secretory rate of the hormone itself but the degree of activity of the target tissue

regulation of gene transcription and translation steps involved in the synthesis of hormones and steps involved in processing hormones or releasing stored hormones

positive feedback – LH, oxytocin cyclical variations – seasonal changes,

various stages of development and aging, the diurnal (daily) cycle, and sleep

Transport of Hormones in Blood

water-soluble hormones (peptides and catecholamines) – dissolved in the plasma

steroid and thyroid hormones – circulate in the blood mainly bound to plasma proteins (usually less than 10% free in solution), biologically inactive (serve as reservoirs, greatly slows their clearance from the plasma)

Clearance of Hormones from Blood

concentration of a hormone in the blood:

1) rate of hormone secretion into the blood

2) rate of removal of the hormone from the blood (metabolic clearance rate – number of milliliters of plasma cleared of the hormone per minute)

one measures : the rate of disappearance of hormone from the plasma & concentration

1) metabolic destruction by the tissues2) binding with the tissues3) excretion by the liver into the bile4) excretion by the kidneys into the urine liver damage excessively high

concentration of steroid hormones half-life of angiotensin II < 1 minute,

thyroid hormones 1-6 days

Hormone Receptors and Their Activation binding to specific receptors at the target

cell – first step of a hormone's action initiation of a cascade of reactions in the

cell – amplification of the effect hormonal receptors are large proteins, each

cell usually has some 2000 to 100,000 receptors

receptor is highly specific for a single hormone

1) in or on the surface of the cell membrane (protein, and catecholamine hormones)

2) in the cell cytoplasm (steroid hormones)

3) in the cell nucleus (thyroid hormones) number of receptors usually does not

remain constant (increase or decrease)

Intracellular Signaling

formation a hormone-receptor complex – alteration of function of receptor :

1) ion channel-linked receptors

2) G protein-linked hormone receptors

3) enzyme-linked hormone receptors

4) intracellular hormone receptors and activation of genes

1) Ion Channel-Linked Receptors

acetylcholine & norepinephrine change in the structure of the receptor opening or closing a channel for one or

more ions (Na, K, Ca) few directly, most indirectly by coupling

with G protein-linked or enzyme-linked receptors

2) G Protein-Linked Hormone Receptors

heterotrimeric GTP-binding proteins > 1000 known G protein-coupled receptors all have 7 transmembrane segments that

loop in and out of the cell membrane cytoplasmic tail is coupled to G protein

(include three parts – α, β, and γ subunits) binding of hormone – conformational

change in receptor – activation of G protein

activated G proteins1) open or close cell membrane ion channels

2) change the activity of an enzyme in the cytoplasm

G proteins binds GDP (α subunit) displacement of GDP by GTP causes the α

subunit to dissociate from the trimeric complex and to associate with other intracellular signaling proteins

inhibitory (Gi) & stimulatory (Gs) proteins

3) Enzyme-Linked Hormone Receptors

some receptors, when activated, function directly as enzymes or are closely associated with enzymes that they activate

pass through the membrane only once hormone-binding site on the outside of the

cell membrane

catalytic or enzyme-binding site on the inside

leptin receptor member of a large family of cytokine receptors that do

not themselves contain enzymatic activity but signal through associated enzymes

one of the signaling pathways occurs through a tyrosine kinase of the janus kinase (JAK) family, JAK2

4) Intracellular Hormone Receptors and Activation of Genes

steroid hormones, thyroid hormones, retinoid hormones, and vitamin D

receptors in the cytoplasm or nucleus binding with a specific regulatory

(promoter) sequence of the DNA – hormone response element

transcription of specific genes and formation of mRNA

Second Messenger Mechanisms

cAMP, cGMP calcium ions and associated calmodulin

4 binding sites for Ca, 3 or 4 changes its shape activation/inactivation of protein kinases phosphorylation of proteins (myosin light

chain kinase – smooth muscle contraction) products of membrane phospholipid

breakdown

could beGi

amplificationof the effect – cascade of reactions

phosphatidylinositol biphosphate

contraction,secretion

Steroid Hormones Increase Protein Synthesis

these proteins then function as enzymes, transport proteins, or structural proteins

aldosterone – for 45 minutes, protein which promote sodium reabsorption and potassium secretion

full action is delayed for at least 45 minutes-up to several hours or even day

Thyroid Hormones Increase Gene Transcription in the Cell Nucleus

thyroxine and triiodothyronine bind directly with receptor proteins in the

nucleus (activated transcription factors located within the chromosomal complex)

they control the function of the gene promoters

formation of many types of intracellular proteins

thyroid hormones can continue to express their control functions for days or even weeks

Measurement of Hormone Concentrations in the Blood extremely minute quantities (pg/mL) radioimmunoassay

production of antibody that is highly specific for the hormone to be measured is produced

small quantity of this antibody (smaller than total possible) is mixed with:

1) sample containing the hormone to be measured

2) appropriate amount of purified standard hormone that has been tagged with a radioactive isotope

error of 10 to 15 percent

Measurement of Hormone Concentrations in the Blood

ELISA (enzyme-linked immunosorbent assay)

1) it does not employ radioactive isotopes

2) much of the assay can be automated using 96-well plates

3) cost-effective and accurate method for assessing hormone levels