Download Physiology Ch 74 p881-892 [4-25

Physiology Ch 74 p881-892
Introduction to Endocrinology
There exist several types of chemical messenger systems in the body
1. Neurotransmitters – released by axons into synapses to act locally to control nerve functions
2. Endocrine Hormones – released by glands into the blood and influence target cells elsewhere
3. Neuroendocrine Hormones – secreted by neurons into blood to influences cells elsewhere
4. Paracrines – secreted by cells into extracellular fluid and affect neighboring cells
5. Autocrines – secreted by cells into extracellular fluid to affect the same cells producing them
6. Cytokines – peptides secreted into extracellular fluid and can function as para- or autocrines
a. Examples include interleukins, lymphokines, leptin, adipokines
Three classes of hormones exist:
1. Proteins and Polypeptides – ant/post pituitary, pancreas, parathyroid gland
2. Steroids – secreted by adrenal cortex, ovaries, testes, and placenta
3. Amines – come from tyrosine, secreted by thyroid, adrenal medulla
Gland/Tissue
Hormone
Functions
Structure
Hypothalamus
Thyrotropin-releasing
hormone (TRH)
Corticotropin-releasing
hormone (CRH)
Secretion of thyroid-stimulating
hormone + prolactin
Peptide
Release of adrenocorticotropic
hormone (ACTH)
Peptide
Hypothalamus
Growth Hormone Releasing
Hormone (GHRH)
Release of growth hormone
Peptide
Hypothalamus
Inhibits release of growth
hormone
Peptide
Release of Leutenizing (LH) and
follicle-stimulating (FSH) horm.
Peptide
Inhibits release of prolactin
Amine
Anterior Pituitary
Anterior Pituitary
Anterior Pituitary
Anterior Pituitary
Growth hormone
inhibitory hormone GHIH
Gonadotropin-releasing
hormone (GnRH)
Dopamine/prolactin
inhibiting factor (PIF)
Growth Hormone
TSH
ACTH
Prolactin
Protein synthesis/growth
Peptide
Peptide
Peptide
Peptide
Anterior Pituitary
FSH
Anterior Pituitary
LH
Posterior Pituitary
Antidiuretic Hormone (ADH)
Posterior Pituitary
Oxytocin
Adrenal Cortex
Cortisol
Thyroid
Thyroid
Adrenal Cortex
Thyroxine (T4) and
Triiodothyronine (T3)
Calcitonin
Aldosterone
Adrenal Medulla
Pancreas
Norepinephrine/epinephrine
Insulin (B cells)
Hypothalamus
Hypothalamus
Hypothalamus
Synthesis/thyroid hormones
Synthesis/adrenocorticoids
Development of breasts and
milk production
Growth of follicles in
ovaries/sperm maturation
Ovulation/testosterone
synthesis, forms corpus luteum
estrogen/progest. synthesis
Increases H2O absorption in
kidneys and vasoconstriction
and increase BP
Milk ejection from breasts and
uterine contractions
Metabolism of proteins, carbs,
fats, anti-inflammatory effect
Increases rates of chemical
reactions/metabolic rate
Deposition of Ca on Bones
Increase renal Na absorption, K
secretion and H secretion
Sympathetic stimulation
Glucose entry into cells
Peptide
Peptide
Peptide
Peptide
Steroid
Amine
Peptide
Steroid
Amine
Peptide
Gland/Tissue
Hormone
Functions
Structure
Pancreas
Parathyroid Gland
Glucagon (α cells)
Parathyroid Hormone (PTH)
Synthesis of glucose in liver
Peptide
Peptide
Testes
Testosterone
Ovaries
Ovaries
Estrogens
Progesterone
Placenta
Human chorionic
gonadotropin (HCG)
Human
Somatomammotropin
Estrogens
Progesterone
Renin
Placenta
Placenta
Placenta
Kidney
Stomach
1,25dihydrooxycholecaliferol
Erythropoietin
Atrial natriuretic Peptide
(ANP)
Gastrin
Small Intestine
Secretin
Small Intestine
Cholecystokinin (CCK)
Adipocytes
Leptin
Kidney
Kidney
Heart
Controls serum Ca concentration by
absorbing Ca in gut and kidneys and
releasing Ca from bones
Development of male reproductive
system and 2nd sex character.
Female reproductive system, breasts
Secretion of uterine milk and
development of breast secretion
Growth of corpus luteum and
secretion of estrogens + progest.
Steroid
Steroid
Steroid
Peptide
Promote development of fetal
tissues as well as breasts
Peptide
Female reproduction
Steroid
Steroid
Peptide
Secretion of uterine milk….
Conversion of angiotensinogen to
angiotensin I
Increases intestinal absorption of Ca
and bone mineralization
Increases erythrocyte production
Increases Na excretion by kidneys,
reduces BP
Stimulates HCl secretion by parietal
cells
Stimulates pancreatic acinar cells to
secrete HCO3 and H2O
Gallbladder contraction and release
of pancreatic enzymes
Inhibits appetite, stimulates
thermogenesis
Steroid
Peptide
Peptide
Peptide
Peptide
Peptide
Peptide
Polypeptide Hormones Stored in Secretory Vesicles Until Needed – synthesized on the rough end of
endoplasmic reticulum of endocrine cells
-synthesized as inactive preprohormones that are cleaved to form prohormones in ER
-transferred to golgi for packaging into vesicles, being cleaved here into hormones
-vesicles stored in cytoplasm bound to cell membrane until secretion by exocytosis (fusion with memb.)
-stimulus for exocytosis is usually cytosolic increase in Ca concentration by depolarization of membrane
-Can also be caused by increased cAMP and kinase activity
Steroid Hormones are Synthesized from Cholesterol and are NOT stored – lipid soluble consisting of
three cyclohexyl rings and one cyclopentyl ring combined
-very little hormone storage in endocrine cells, but large stores of cholesterol-esters can be stored in
vacuoles in cytoplasm for quick steroid synthesis after a stimulus
-cholesterol comes from plasma but can also be synthesized, and hormones can easily cross membrane
Amine Hormones are Derived from Tyrosine – Thyroid and adrenal medullary hormones formed by
enzymes in cytoplasmic compartments of glandular cells
-thyroid hormones synthesized by thyroid and incorporated into macromolecule protein thyroglobulin,
stored in follicles within thyroid gland
-secretion occurs when amines are split from thyroglobulin and free hormones enter blood
-In the blood, they combine with plasma proteins (thyroxine-binding globulin) slowly releasing
hormones to tissues
-Adrenal medulla forms epinephrine and norepinephrine, secreting 4x more epinephrine: taken up into
preformed vesicles and stored until secreted by exocytosis into blood where they are in free form
Hormone Secretion, Transport, and Clearance from the Blood – some hormones are secreted within
seconds after a gland is stimulated (epinephrine/norepinephrine), and act within minutes.
-Others, such as thyroxine and GH can take months for full effect
Concentrations of Hormones in Circulating Blood – concentrations of hormones needed is low, can
range from 1 picogram in each mL of blood to a few micrograms in each mL
Negative Feedback Prevents Overactivity – hormones are closely controlled, mostly though negative
feedback mechanisms.
-After stimulus causes release of hormone, conditions or products resulting from action of that hormone
suppress its further release
-Only when target tissue activity rises to an appropriate level will feedback signals to endocrine gland be
powerful enough to slow further secretion
-Can occur at gene level, transcription, or translation
Surges of Hormones Can Occur with Positive Feedback – positive feedback occurs when action of
hormone causes more secretion of the hormone, such as with Luteinizing Hormone (LH) that occurs as a
result of estrogen on anterior pituitary before ovulation.
-LH is released causing more estrogen secretion, causing more LH until a point of negative feedback is
reached
Cyclic Variations Occur in Hormone Release – seasonal changes can influence hormone release apart
from negative and positive feedback mechanisms, such as sleep, diurnal cycle, and age
-due to changes in neural pathways involved in controlling hormone release
Transport of Hormones in the Blood – Water-soluble hormones dissolved in plasma and transported to
their sites of synthesis to target tissues to diffuse into capillaries, interstitial fluid and target cells
-Steroid and Thyroid hormones circulate bound to plasma proteins and are not active until they
dissociate from proteins
Two factors can increase or decrease hormones in blood:
1. Rate of hormone secretion in blood
2. Rate of removal of hormone from blood (metabolic clearance rate) expressed in mL of plasma
cleared of hormone per minute
a. Calculate rate of disappearance of hormone and plasma concentration of hormone in
blood
b. Metabolic clearance rate = rate of disappearance / concentration of hormone
-Hormones cleaved from plasma by several ways, including metabolic destruction by tissues, binding
with tissues, excretion by liver into bile, and excretion by kidneys into urine
-For some hormones, decreased metabolic clearance causes excessively high concentration, such as
several steroid hormones when liver is diseased and not able to clear hormone into bile
-Peptide hormones freely soluble and degraded by enzymes in blood and tissues to be excreted by
kidneys and liver (half life for angiotensin II is 1 minute)
-Hormones bound to plasma proteins are cleared at a much slower rate – adrenal steroids half life is 20100 minutes whereas thyroid hormones may be 1-6 days
Mechanism of Hormone Action
-First step of hormone’s action is binding to specific receptors on target cell, some on membrane and
some inside the cytoplasm
-binding of hormone to receptor initiates a cascade of reactions becoming more powerful
-hormone receptors are large proteins and specific for a single hormone
-can be found on cell surface (peptide, catecholamine), cytoplasm (steroid), and nucleus (thyroid)
Hormone Receptors are Regulated – number of receptors does not remain constant, and can be
inactivated or destroyed during course of function and later reactivated or resynthesized
-Down-regulation can result from inactivation of some receptor molecules, inactivation of some
intracellular protein signaling molecules, sequestration of receptor inside of cell away from membrane,
destruction of receptors, and decreased production of receptors
-Up-regulation of receptors and intracellular signaling proteins causes more sensitivity to hormone
Intracellular Signaling After Hormone Activation – hormone-receptor complex changes function of
receptor to activate hormonal effects
1. Ion Channel-Linked receptors – all neurotransmitters such as acetylcholine and norepinephrine
combine with receptors postsynaptically causing conformational changes and opening or closing
of receptors for Na, K, Ca, or others, causing flow through and subsequent downstream effects
2. G Protein-linked Hormone Receptors – many hormones activate receptors coupled with
heterotrimeric GTP-binding proteins (G proteins) which all have 7 transmembrane segments
that loop in and out of cell membrane
a. Intracellular components include three subunits, α, β, and γ.
b. When hormone binds extracellular receptor, conformation change activates G protein
to open close ion channels or change activity of enzymes in the cell
c. G proteins can bind guanosine nucleotides. In inactive state, α, β, and γ complex binds
GDP on α subunit
d. Upon receptor binding, conformational change causes exchange of GDP for GTP, causing
α subunit dissociation from complex and associate with other intracellular signaling
molecules such as adenylyl cyclase or phospholipase C.
e. Signaling is terminated when hormone is removed and α subunit inactivates by
converting GTP to GDP and combines with β and γ subunits to make the complex
-G proteins can be inhibitory or stimulatory depending on the hormone
Enzyme-Linked Hormone Receptors – some receptors function as enzymes when activated
-have 1 membrane spanning domain, outside binds hormone, inside has catalytic domain
Leptin receptor is an example of Enzyme-linked hormone receptor, signaling occurs through a tyrosine
kinase of the janus kinase (JAK) family, JAK2. Receptor exists as dimer
1. Binding of leptin to receptor causes conformational change enabling phosphorylation and
activation of JAK2
2. JAK2 then phosphorylate other tyrosine residues within Leptin receptor-JAK2 complex such as
STAT proteins, which when phosphorylated, activate transcription by leptin target genes to
initiate protein synthesis
3. Phosphorylation of JAK2 also leads to activation of other pathways such as MAPK and PI3K
pathways
-Another example used in hormonal control is the receptor that when activated becomes an adenylyl
cyclase in the interior of cell to catalyze formation of cAMP which acts as a second messenger
-Few peptide hormones such as atrial natriuretic peptide uses cGMP as a second messenger
Intracellular Receptors and Activation of Genes – Lipid soluble hormones such as steroid, adrenal,
gonadal, thyroid, retinoid, and vitamin D can cross cell membrane to bind receptors inside the cell
-The hormone-receptor complex binds a specific regulatory promoter sequence on DNA called the
hormone response element and activates or represses transcription.
Second Messenger Mechanisms for Mediating Hormonal Functions – in addition to cAMP, calmodulin
and phospholipid breakdown products at as second messengers
1. cAMP Second Messenger – binding of hormone to receptor couples receptor to Gs (stimulatory)
protein which stimulates adenylyl cyclase-cAMP system, which catalyzes converstion of ATP to
cAMP inside cell.
a. cAMP activates cAMP-dependent protein kinase to phosphorylate proteins inside cell
b. Activates a cascade of enzymes, where one can activate multiple, and so forth.
c. ACTH, calcitonin, catecholamines, CRH, FSH, glucagon, HCG, LH, PTH, etc.. use cAMP
-if binding of hormone causes an inhibitory G protein cascade (Gi), adenylyl cyclase would be
inhibited, causing reduced cAMP and reduced effects in cell
-thyroid cell stimulated by cAMP forms thyroxine and triiodothyronine, whereas cAMP in
adrenocortical cells causes secretion of adrenal steroid hormones
-in renal tubules, cAMP increases their permeability to H2O
2. Phospholipid Second Messenger – some hormones activate transmembrane receptors to
activate enzyme phospholipase C
a. Phospholipase C catalyzes breakdown of membrane lipids such as phosphatidylinositol
biphosphate (PIP2) into two second messengers inositol triphosphate (IP3) and
diacylglycerol (DAG)
b. IP3 mobilizes Ca ions from mitochondria and ER and act to contract smooth muscle and
change cell secretion
c. DAG activates protein kinase C (PKC), phosphorylating large number of proteins leading
to a cellular response
i. Lipid portion of DAG is arachidonic acid, precursor to prostaglandins and other
local hormones
3. Calcium-Caldmodulin Second Messenger – Entry of Ca ions into cells is a second messenger and
is initiated by changes in membrane potential with open Ca channels or a hormone interacting
with membrane receptors to open channels
a. Ca enters the cell and binds with the protein calmodulin (4 Ca sites on it). When 3-4
sites have been bound, calmodulin undergoes conformational change and initiates
effects such as activation or inhibition of kinases
b. Calmodulin-dependent kinases phosphorylate to cause activation or inhibition of
proteins involved in cells response to hormone
i. Calmodulin can activate Myosin light chain kinase, acting on smooth muscle to
cause contraction
-Normal Ca levels in cell are 10^-8 or 10^-7, not enough to activate calmodulin, which needs a
concentration of 10^-6 or -5. This is the same amount of calcium required to activate troponin C
in skeletal muscle
Hormones that Act on Genetic Machinery –
-Steroid hormones from adrenal cortex, ovaries, and testes cause synthesis of proteins in target
cells to function as enzymes, transport or structural proteins
1. Steroid hormone diffuses across membrane and enters cytoplasm of cell to bind to
receptor
2. Receptor-protein-hormone diffuses into nucleus and binds DNA to activate transcription
3. mRNA diffuses into cytoplasm to be translated on ribosomes in protein
-Aldosterone is secreted by adrenal cortex enters cytoplasm of renal tubular cells and
binds to mineralocorticoid receptor to promote Na reabsorption from tubules
-Thyroid hormones increase transcription in the nucleus
-thyroxine and triiodothyronine cause increased transcription of genes in nucleus by
binding to receptors in nucleus called activated transcription factors within
chromosomal complex
-two important features of thyroid hormone function in nucleus are:
1. Activate genetic mechanisms for formation of intracellular proteins for
metabolic activities
2. Once bound to intranuclear receptors, thyroid hormones continue to express
their control for days or even weeks
Measurement of Hormone Concentrations in Blood – uses sensitive method called the
radioimmunoassay developed 45 years ago
Radioimmunoassay – antibody specific for hormone is produced and mixed with fluid from animal
containing hormone to be measured and simultaneously mixed with appropriate amount of purified
standard hormone tagged with radioactive isotope
-must be too little antibody to bind completely both radio-tagged and fluid.
-natural hormone and tagged hormone compete for antibody
-If large amount of radioactive hormone is found, it means there wasn’t as much natural hormone to
compete with it from fluid, and vice versa
Enzyme-linked Immunosorbent Assay – ELISA can measure almost any protein, combining antibodies
with simple enzyme assays performed on plastic plates
-plate has enzyme attached specific for hormone, samples are added to each wells followed by a second
antibody also specific for hormone but binds to a different region on hormone
-third antibody is added that recognizes the second antibody coupled to an enzyme that converts a
suitable substrate to a product that can be detected by colorimetric or fluorescent methods