1. Introduction to Endocrinology
Prof. dr. Zoran Valić
Department of Physiology
University of Split School of Medicine

2. Coordination of Body Functions
nervous system (neurotransmitters into the synaptic junctions – locally)
endocrine system (hormones into blood)
neuroendocrine (neurohormones into blood)
paracrines (secreted into extracellular fluid and affect neighboring different target cells)
autocrines (affect same cells)
cytokines (peptides - 5,4 or 2 - interleukins, lymphokines, adipokines (leptin))

3. 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

5. Chemical Structure and Synthesis
proteins and polypeptides
steroids
derivatives of the amino acid tyrosine (thyroid and the adrenal medullae)
there are no known polysaccharides or nucleic acid hormones

6. 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)

8. 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

10. 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

11. 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 to 10-6g/ml) – rates of secretion are extremely small (μg-mg/day)

12. 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

13. 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

14. 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)

15. Clearance of Hormones from Blood
concentration of a hormone in the blood:
rate of hormone secretion into the blood
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

17. metabolic destruction by the tissues
binding with the tissues
excretion by the liver into the bile
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

18. 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

19. in or on the surface of the cell membrane (protein, and catecholamine hormones)
in the cell cytoplasm (steroid hormones)
in the cell nucleus (thyroid hormones)
number of receptors usually does not remain constant (increase or decrease)

20. Intracellular Signaling
formation a hormone-receptor complex – alteration of function of receptor :
ion channel-linked receptors
G protein-linked hormone receptors
enzyme-linked hormone receptors
intracellular hormone receptors and activation of genes

21. 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

22. 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

23. G proteins binds GDP (α subunit)
activated G proteins
open or close cell membrane ion channels
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

25. 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

26. 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

28. 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

30. 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

32. could be Gi
amplification
of the effect –
cascade of
reactions

34. phosphatidylinositol
biphosphate
contraction,
secretion

35. 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

36. 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

37. formation of many types of intracellular proteins
thyroid hormones can continue to express their control functions for days or even weeks

38. 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:
sample containing the hormone to be measured
appropriate amount of purified standard hormone that has been tagged with a radioactive isotope
error of 10 to 15 percent

40. Measurement of Hormone Concentrations in the Blood
ELISA (enzyme-linked immunosorbent assay)
it does not employ radioactive isotopes
much of the assay can be automated using 96-well plates
cost-effective and accurate method for assessing hormone levels