Download Endocrine Physiology

ENDOCRINE
PHYSIOLOGY
ENDOCRINE GLANDS
BASIC PRINCIPLES AND
ORGANIZATION
Definition of the Endocrine System
•Endocrine and nervous systems coordinate
complex body functions.
•Classic distinction between these two is that the
endocrine system communicates to distant tissues
through blood-carried chemicals while the nervous
system communicates to adjacent tissue by local
chemical release (neurotransmitter，
•Organs of the endocrine system include adrenal,
gonads, hypothalamus, pancreas, parathyroid,
pituitary, thyroid, as well as others, such as the
heart, kidney, and gastrointestinal tract.
Distinction between these two
communication systems
—Nervous system and Endocrine system
• Nerves in the posterior pituitary release oxytocin
and antidiuretic hormone, which act on the breast
and kidneys, respectively;
• Nerves release epinephrine from the adrenal
medulla, which acts on the heart, skeletal muscle,
and the liver;
• Nerves of the hypothalamus secrete chemicals
(releasing hormones) that act on the anterior
pituitary to cause hormone release.
• Therefore, the definition of the endocrine system
should also include such neuroendocrine systems.
General definition for hormone
•Classic definition ( By Starling and Bayliss)
The hormones are chemical substances produced by
specialized tissues and secreted into blood, in which
they are carried to target organs and triggers specific
biological functions.
•Limits of classic definition:
Specialized tissues for hormone synthesis
Blood for hormone distribution
A separate target organ
•Broader definition
A hormone is a chemical non-nutrient, intercellular
messenger that is effective at micromolar
concentrations or less (high efficiency).
A further understanding on
hormones
•Living things that can secrete homones
Multicelluar: Animal, Plant, Insect and Some fungi.
•Concentration
Peptidal hormone in animal blood
10-12~10-10 M,
Steroid hormone in animal blood 10-10~10-8 M.
•Endocrine cell and Target Cell, tissue and organ.
•Powerful Biological Effects
Metabolic and Physiological effect.
TABLE ENDOCRINE GLANDS, HORMONES SECRETED, AND TISSUE EFFECT
ENDOCRINE GLAND
Hypothalamus
HORMONES SECRETED
TISSUE EFFECT
Corticotropin-releasing hormone (CRH)
Dopamine
Stimulates ACTH secretion
Inhibits prolactin secretion
Gonadotropin-releasing hormone (GnRH)
Stimulates LH and FSH secretion
Growth-hormone releasing hormone (GHRH) Stimulates GH secretion
Somatostatin
Inhibits GH secretion
Thyrotropin-releasing hormone (TRH)
Stimulates TSH and prolactin
secretion
Anterior
Adrenocorticotropic hormone (ACTH)
Stimulates synthesis/secretion
pituitary
of cortisol, androgens and
aldosterone
Follicle- stimulating hormone (FSH)
Stimulates sperm maturation;
development of ovarian follicles
Growth hormone (GH)
Stimulates protein synthesis and
growth
Luteinizing hormone (LH)
Stimulates testosterone,
estrogen, progesterone
synthesis; stimulates ovulation
Melanocyte-stimulating hormone (MSH)
Stimulates melanin synthesis
Prolactin
Stimulates milk production
Thyroid-stimulating hormone (TSH)
Stimulates thyroid hormone
synthesis/secretion
Posterior
Oxytocin
Pituitary
Stimulates milk ejection and
uterine contraction
Antidiuretic hormone (ADH)
Stimulates renal water
reabsorption
Thyroid
Triiodothyronine (T3) and
thyroxine (T4)
Stimulates growth, oxygen
consumption, heat production,
metabolism, nervous system
development
Continued next
TABLE ENDOCRINE GLANDS, HORMONES SECRETED, AND TISSUE EFFECT (continued)
ENDOCRINE GLAND
HORMONES SECRETED
TISSUE EFFECT
Thyroid
Calcitonin
Decreases blood Ca concentration
Parathyroid
Parathyroid hormone (PTH)
Increases blood Ca concentration
Adrenal cortex
Cortisol
Increases glucose synthesis;
mediates “stress” response
Aldosterone
Increases renal reabsorption of
Na+, secretion of K+, and H+
Androgens
Similar to testosterone but
weaker
Adrenal medulla
Epinephrine
Stimulates fat and carbohydrate
metabolism
Pancreas
Insulin
Decreases blood glucose levels;
anabolic effects on lipid and
protein metabolism
Glucagon
Increases blood glucose levels
Testes
Testosterone
Stimulates spermatogenesis and
secondary sex characteristics
Ovaries
Estradiol
Stimulates growth/development
of female reproductive system
and breasts, follicular phase of
menstrual cycle, prolactin
secretion, and maintains
pregnancy
Progesterone
Luteal phase of menstrual cycle
and maintains pregnancy
Corpus luteum
Estradiol and progesterone
See above
Placenta
Human chorionic gonadotropin (hCG) Stimulates estrogen/progesterone
synthesis by corpus luteum
Human placental lactogen (hPL)
Acts like GH and prolactin during
pregnancy
Estriol
Acts like estradiol
Progesterone
See above
This table lists the major endocrine organs, the hormones each organ secretes, and the major tissue effect of
the hormone.
ENDOCRINE SYSTEM
Chemical Nature of Hormones
•Classic definition of a hormone is a chemical
produced by an organ in a small amount that is
released into the blood stream to act on cells in a
distant tissue.
•This definition needs to be expanded to include
chemicals that have paracrine and autocrine
functions.
•Hormones are divided into four groups based on
chemical structure:
(1) amines，胺类 (come from the amino acid tyrosine),
(2) peptides，肽类 (less than 20 amino acids),
(3) small proteins，小蛋白 (more than 20 amino acids),
(4) steroids，类固醇 (come from cholesterol).
Definition of the hormones
Telecrine signals
Neurocrine signals
Definition of the hormones
Endocrine Cell
Receptor
Target Cell
Paracrine Cell
Endocrine
hormone
Target Cell
Paracrine
Hormone
Blood Flow
Paracrine
Hormone
Target Cell
Autocrine Cell
Autocrine
Hormone
Hormone have four groups based on its chemical structure
TABLE
MAJOR HORMONES GROUPED BY CHEMICAL STRUCTURE
AMINES
PEPTIDES
Dopamine
Antidiuretic
PROTEINS
Adrenocorticotropic
hormone (ADH)
Epinephrine
STEROIDS
Aldosterone
Hormone (ACTH)
Gonadotropin- releasing
Calcitonin
Cortisol
hormone (GnRH)
Thyroxine
(T4)
Triiodothy-
Melanocyte-Stimulating
hormone (MSH)
Human chorionic
Estradiol
gonadotropin (hCG)
Oxytocin
Human placental
ronine (T3)
Estriol
lactogen (hPL)
Thyrotropin-releasing
Corticotropin-releasing
Hormone (TRH)
hormone (CRH)
Somatostain
Glucagon
Growth hormone (GH)
Growth hormone-releasing hormone (GHRH)
Follicle-stimulating hormone (FSH)
Insulin
Insulin-like growth factor (IGF-1)
Luteinizing hormone (LH)
Parathyroid hormone (PTH)
Prolactin
Thyroid-stimulating hormone (TSH)
This table groups the major hormones according to their chemical composition
Progesterone
Testosterone
1,25-vitamin D
Mechanism of Hormone Action
• Hormones act through specific receptors that define
tissue selectivity and response.
• Receptors for amine, protein, and peptide hormones
are located on the cell membrane, while those for
steroid and thyroid hormones are within the cell.
• Membrane receptors are of four types based on their
signaling mechanisms: G protein, tyrosine kinase,
guanylyl cyclase, cytokine family.
• Steroid and thyroid hormones act through nuclear
receptors that stimulate gene expression.
• Membrane-receptor mediated hormones elicit rapid
(minutes) cellular responses; nuclear-receptor
mediated hormones elicit slow (hours), long lasting
cellular responses (because of slow protein
degradation).
Four Types of the Membrane Receptors Based on Their
Intracellular Signaling Mechanisms
TABLE
HORMONES SIGNALING THROUGH MEMBRANE
RECEPTORS
G - Protein Receptors Linked to:
Adenylyl
Phospho-
Tyrosine Kinase
Cyclase
lipase C
Receptors
ACTH,
ADH,
Insulin,
Calcitonin,
GHRH,
Insulin-like
CRH,
GnRH,
growth
Dopamine
Oxytocin,
factor-1
Epinephrine,
TRH
Guanylyl Cyclase
Cytokine Receptor
Receptors
ANP
(IGF-1)
FSH,
Glucagons,
hCG,
LH,
MSH,
PTH,
Somatostatin,
TSH
This table groups the major hormones according to their signaling mechanisms.
Family
GH,
prolactin
A Combination of Hormone and
Receptor
Hormone
Receptor
Hormone
Receptor
Changes in conformation of hormone combining with receptor
A: Changes in configuration of receptor induced by hormone
B: Changes in configuration of hormone induced by receptor
A Combination of Hormone and
Receptor
Complex of Hormone and
Receptor
or receptor
Labeled
Unlabeled
Complex
Labeled
Unlabeled
Receptor quantity limit combination of
hormone and receptor
Receptor quantity limit combination of
hormone and receptor
C
o
m
bi
n
at
io
n
of
A
b
a
n
d
A
g
Components of Membrane
Receptors
Membrane receptors consist of three components:
(1) an extracellular domain that binds the hormone;
(2) a transmembrane domain that anchors it in the
membrane;
(3) an intracellular domain that couples the receptor
to an intracellular signaling system.
It was evidenced that For the G-protein coupled
receptors, the transmembrane domain loops back and
forth through the membrane 7 times, while for others it
passes through only once. When the hormone stimulates
the receptor, an intracellular signaling system is
activated that initiates a cascade of cellular events
culminating in the hormone response.
The structure of G-protein
G-protein
Receptor
Enzyme
Receptor
The structure of G-protein coupled receptors
Carbohydrate group of
glycoprotein
Outside cell
Receptor of
transmembrane
7 times
Cell membrane
Inside cell
Combining position
of phosphorylation
Interaction between the Hormones, Receptors and
G-proteins
Basic status
Receptor activation
GTPase
Subunits disassociation
Reactor activation
R: receptor; E: enzyme; H: hormone; S: substance; P: product
Signal conductive mechanism of
G-protein linked membrane receptors
• G-protein linked receptors have the characteristic of being
linked to an intracellular class of proteins called G proteins.
• G proteins are a cluster of three proteins (subunits) that,
when activated by hormone binding to the extracellular
domain of the receptor, cause stimulation of one of two
enzymes, adenylyl cyclase (腺苷环化酶AC) or phospholipase C.
• Activation of AC leads to the formation of cyclic adenosine
monophosphate (cyclic AMP, cAMP), and activation of
phospholipase C leads to the formation of inositol
trisphosphate (IP3) or diacylglyercerol (DAG or DG), or
activation of protein kinase C (蛋白激酶C, PKC).
• These named second messenger molecules initiate a cascade
of events culminating in the hormone response.
Signal transduction mechanism of
G-protein coupled receptors
ACTH, Calcitonin, CRH, Dopamine, FSH, Glucagon, hCG, LH, MSH, PTH,
Somatostatin, TSH
R: Regulative subunit
C: catalysis subunit
Physiological and Biochemical function
Cascade of events culminating in
the hormone response
Effects of Adenylyl Cyclase (AC) Receptors
Signal transduction of G-protein coupled receptors
ACTH, Calcitonin, CRH, Dopamine,
Epinephrine, FSH, Glucagon, hCG,
LH, MSH, PTH, Somatostatin, TSH
Cell membrane
Protein
Protein
phosphorylation
Biological function
Mechanism of hormone acting on membrane receptor
H: hormone; R: receptor; GP: G-protein; AC: adenylyl cyclase; PDE: phosphodiesterase; PKr: protein
kinase regulative subunit; PKc: protein kinase catalysis subunit
Theory of the Second Messengers
For G-protein coupled Receptor
Cell membrane
Physiological and
Biochemical Functions
Hormone
Hormone
AC: Adenylyl cyclase;
R: regulative part in
the receptor;
C: part for reaction
Protein phosphorylation
Glycogen decomposition
Adenylyl cyclase
Hormone
AC
Inactive
protein
kinase
Fat decomposition
Steroid Hormones synthesis
Second
Messenger
Active
protein
kinase
Histone-nucleic acid synthesis
Nuclein-protein synthesis
Membrane protein-membrane
permeability
Canaliculus secreted
movement
Principle of hormone acting on membrane receptor
Working Mechanism of Phospholipase C Receptor
Hormone (ADH, GHRH, GnRH, OXT, TRH)
Receptor
G-protein
Cell membrane
Phospholipase C
Endoplasmic
reticulum
Second Messenger
Physiological and Biochemical reaction
Signal transduction processes of phospholipid acyl inositol
PIP2: phospholipid acyl inositol disphosphate; DG: diacylglyercerol; IP3: inositol trisphosphate; PKC: protein kinase
C; CaM: calcium-mediated protein
Effects of Guanylyl Cyclase (GC)
Receptors
• The guanylyl kinase receptors (on the
membrane, combined with ANP) have the
enzyme guanylyl cyclase（尿苷酸激酶） as a
portion of their intracellular domain.
Binding of hormone to the extracellular
domain leads to activation of guanylyl
cyclase and the formation of cyclic
guanosine monophosphate (cyclic GMP or
cGMP). This second messenger initiates
the hormone response.
Formation and Mechanism of Several Second
Messengers
Cyclic adenosine
monophosphate (cAMP)
Cyclic guanosine
monophosphate (cGMP)
Inositol trisphosphate
(IP3)
Diacylglyercerol
Release
Regulative
subunit
catalysiss
ubunit
Protein kinase A (PKA)
Protein kinase
Protein
G (PKG)
kinase C (PKC)
PK
R: receptor; Rs: stimulative receptor; Ri: inhibitory receptor; G: G-protein; Gs: stimulative G-protein;
Gi: inhibitory G-protein; AC: adenylyl cyclase; GC: guanylyl cyclase; PC: phospholipase C; CaM:
calcium-modulated protein; Tn: troponin C. (DG is actually in the cell membrane)
Effects of Tyrosine Kinase (TK)
Receptors
• The tyrosine kinase（酪氨酸激酶）
receptors are distinguished by having
an intracellular domain that
phosphorylates proteins on specific
tyrosine molecules. These tyrosinephosphorylated proteins act as second
messengers to initiate a cascade of
events leading to hormone response.
Mechanism of Tyrosine Kinase
(TK) Receptors
Insulin, IGF-1
Receptors
Receptors
Hormone
Outside cell
Cell membrane
Active tyrosine
kinase (TK)
Inactive tyrosine
kinase (TK)
Inside cell
Second Messenger
Mechanisms of Hormone Acting on
Membrane Receptors (summing-up)
Effects of Cytokine Receptors Family
• Cytokine receptor family is distinguished by
the fact that receptor (on the membrane,
combined with GH, Prolactin) activation
indirectly leads to intracellular protein
tyrosine phosphorylation. Hormone binding to
the extracellular receptor domain enables the
intracellular domain to bind soluble tyrosine
kinases called Janus kinases (or JAK kinases).
Binding activates the JAK kinases, which
phosphorylate intracellular proteins and
produce the hormone response.
Effects of Steroid and Thyroid Hormones
• Steroid and thyroid hormones (primarily T3)
signal through intracellular receptors, which
act solely to initiate gene expression. Both
hormone types diffuse through the cell
membrane to act on their intracellular
receptors. The receptors are protein
molecules that bind to specific DNA
sequences known as hormone response
elements (激素反应元件HRE). The hormonereceptor complex activates the HRE,
initiating DNA transcription leading to
protein synthesis.
Mechanism of Steroid Hormones Effect
—Theory of the Genes Expressions
Cell membrane
Nuclear membrane
Cytoplasmic
receptor
Nuclear receptor
Hormone
Specific mRNA
Ribosome
New produced protein
1.
2.
3.
4.
Structural domain combined with hormone;
Structural domain of signal orientation in the nucleus;
Structural domain combined with DNA;
Structural domain of transcriptional activation
Mechanism of Steroid
Hormones Effect
Cell membrane
Nucleus
Hormone
Receptor
Translation
Transcription
Changes in
receptor
configuration
Specific protein
Metabolic reaction
Mechanism of Steroid Hormones Effect
Mechanisms of T3 and T4 Effects
Cell membrane
Mitochondria
Nucleus
Nucleus
receptor
Transcription
Enzyme
Translation
Specific protein
Synthesis and Release of Hormones
• Peptide and protein hormones are synthesized
from amino acids as prohormones or
preprohormones, which are subsequently modified
and stored in intracellular vesicles until secreted
by exocytosis.
• Amine and steroid hormones are synthesized from
precursor molecules (tyrosine, cholesterol)
present in the blood.
• Thyroid and steroid hormones are not stored in
secretory vesicles, but the amine hormone
epinephrine is.
Synthesis and Release of Peptide
and Protein Hormones
(Rough ER)
Processes from Preprohormone
to Hormone
Processes from Prohormone to
Hormone
Control of Hormone Release
• Most hormones are released in a
pulsatile manner（脉冲式） with a
frequency that varies from minutes to
months and is characteristic of the
hormone.
• Hormone release is influenced in part
by positive and negative feedback
mechanisms, especially the latter.
Control of Hormone Secretion
(Common Mechanism)
Short feedback
Solid line means positive
feedback;
Broken line represents
negative feedback
Super short feedback
Long feedback
Hormone Transport in the Blood
• Amine, peptide, and small protein hormones circulate in a
free form in blood because they are water soluble.
• Steroid and thyroid hormones are carried in the blood
bound to proteins (as carrier, e.g. albumin) because they
are water insoluble.
• Protein binding reduces hormones loss through the kidney
since the protein-hormone complex cannot be filtered.
• Only the free form of the hormone can stimulate tissue
receptors because of the capillary endothelium
permeability.
• Most hormones are removed from the blood by the liver
and kidney shortly after being secreted even though their
tissue effect continues (half-life of hormone，激素的半衰期).
Half-life of hormone in the blood
The rate at which the amount of hormone in blood
decreases is called its half-life. This is the time it takes the
concentration of the hormone to fall to one half of its
previous level. Half-lives vary from minutes for the amine
hormones to hours for steroid and thyroid hormones.
Half-life
Hor
mon
e
con
cent
rati
on
(µg /
L
plas
ma)
HYPOTHALAMUS AND THE
PITUITARY GLAND
General Organization
•Pituitary gland and hypothalamus function in a coordinated
manner to integrate many endocrine glands.
•Pituitary gland is located just below the hypothalamus at
the base of the brain to which it is connected by a short
stalk (named the infundibulum，动脉圆锥).
•Pituitary is divided into anterior and posterior portions.
•Secretion of anterior pituitary hormones is under the
control of hypothalamic releasing hormones.
•Posterior pituitary hormones are synthesized in
hypothalamic nerves whose axons end in the posterior
pituitary where hormone is released into the blood.
HYPOTHALAMUS AND THE
PITUITARY GLAND
Relationship of Hypothalamus and
Anterior Pituitary Gland
(Releasing hormones)
Relationship of Hypothalamus and
Posterior Pituitary Gland
Hypothalamic Hormones Influence
Anterior Pituitary Hormone Secretion
•Six hormones are released from the hypothalamus that
control the release of anterior pituitary hormones: TRH,
dopamine, GnRH, CRH, GHRH, somatostatin.
(1) thyrotropin-releasing hormone (TRH, acts on the
thyrotrophs and lactotrophs stimulating TSH and prolactin
secretion, respectively.
(2) Dopamine inhibits lactotroph secretion of prolactin.
(3) Gonadotropin hormone-releasing hormone (GnRH,
stimulates FSH and LH secretion from the gonadotrophs.
(4) Corticotropin-releasing hormone (CRH， stimulates
corticotroph secretion of ACTH.
(5) Growth hormone-releasing hormone (GHRH， and (6)
somatostatin both act on anterior pituitary somatotrophs with
GHRH stimulating and somatostatin inhibiting GH secretion.
Hypothalamic Hormones Influence the Pituitary
Hormone Secretion
Hypothalamus
ReleasingH
ormones
Vasculature
Posterior
Pituitary
ADH or
Oxytocin
Systemic Circulation
AnteriorP
ituitary
Trophic
Cells
Trophic
Hormones
The hypothalamus
regulates secretions from
both the anterior and
posterior pituitary. In the
anterior pituitary, this is
accomplished through the
release of hypothalamicreleasing factors. In the
posterior pituitary, the
secretion are released
from nerves that originate
in the hypothalamus.
Anterior Pituitary Hormones
• Seven hormones are secreted by groups of anterior
pituitary cell: TSH, FSH, LH, ACTH, MSH, GH,
prolactin.
• Trophic action is the primary effect of anterior
pituitary hormones.
• Anterior pituitary hormones can be organized into
three groups based on chemical and functional
similarities: TSH, FSH, LH (same α-chain and different βchain); ACTH and MSH (derived from
proopiomelanocortin, POMC); GH and prolactin
(straight amino acid chain, about 75% same).
• GH is the main regulator of postnatal growth and
development, and prolactin is the major hormone
responsible for milk production.
Growth Hormone (GH)
• GH is the main regulator of postnatal growth and development.
• GH has effects on metabolism that result from the direct action of GH on
target tissue and effects on growth through GH release of insulin-like growth
factor 1 ( IGF-1, primarily from the liver.
• GH’s metabolic effects include decreased tissue glucose uptake with a
consequential increase in blood glucose levels; increased fat metabolism by
adipose tissue; and increased tissue amino acid uptake. These metabolic
effects lead to an increase in lean body mass and to an elevation in blood
insulin levels.
• IGF-1 stimulates cell division in many tissues especially bone. Its effect on
bone produces linear growth. In addition, IGF-1 stimulates protein synthesis
facilitated by the increased amino acid uptake produced by GH.
• Given these normal effects, it follows that GH deficiency during early
childhood results in a child with a short stature (dandiprat or pygmy) and
excess body fat, while overproduction (acromegaly) results in excess organ
and linear growth (gigantism，
Growth Hormone (GH)
The Regulation of GH secretion
+
(IGF-1)
The control of GH release occurs at both the hypothalamic and anterior pituitary levels
Prolactin (PRL)
• PRL is the major hormone responsible for milk production
(lactogenesis) and is involved in breast development.
• PRL secretion is reciprocally controlled through the stimulatory
actions of TRH (and other yet to be identified hormones) and
the inhibitory effect of dopamine.
• In the nonlactating person, the effect of dopamine dominates so
blood levels of PRL are low. At puberty in the female, PRL
enhances the ability of the elevated levels of estrogen and
progesterone to stimulate breast development.
• During pregnancy, PRL secretion increases, and together with
estrogen and progesterone enhance the development of milkproducing cells in the breast. Despite the high PRL levels, milk
production does not occur because the high levels of estrogen
and progesterone act on the mammary gland to block the
lactogenic effect of PRL. At birth, the mother’s blood levels of
PRL, estrogen, and progesterone fall. The act of suckling
stimulates TRH (or some other factor) and inhibits dopamine
release producing a surge of PRL secretion, which stimulates
milk production.
Posterior Pituitary Hormones
• Posterior pituitary secretes two hormones, oxytocin (OXT)
and antidiuretic hormone (ADH), that are synthesized by
nerves in the paraventricular and supraoptic nuclei (PVN
and SON) of hypothalamus.
• OXT causes milk ejection in response to suckling by
stimulating contraction of myoepithelial cells lining the
ducts leading to the nipples. Sensory receptors in the
nipples signal the brain and hypothalamus causing
activation of nerve cells of the PVN and OXT release. In
addition, OXT stimulates uterine contraction but its role in
parturition is unclear.
• ADH increases water reabsorption by increasing the water
permeability of the collecting duct of the kidney. Further
discussion of its mechanism of action and the control of its
release can be found in Renal Physiology.
THYROID GLAND
General Organization
• Thyroid gland consists of two lobes,
one on either side of the trachea just
below the cricoid cartilage.
• Lobes are composed of spherical
follicles formed by a single layer of
epithelial cells that surround a lumen
filled with a gel-like substance called
colloid composed primarily of
thyroglobulin, the precursor of thyroid
hormones.
• The epithelial cells synthesize and
secrete thyroglobulin.
ANATOMY OF THYROID GLAND
ANATOMY AND HISTOLOGY OF
THYROID GLAND
Synthesis of Thyroid Hormone
• Synthesis includes steps that occur within
the epithelial cells and colloid of the thyroid
gland as well as at the target tissue.
• Iodine uptake and thyroglobulin synthesis
occur within epithelial cells.
• Iodination of thyroglobulin and synthesis of
T3 and T4 occur within the colloid.
• T3, most active form of the hormone, is
produced from T4 at the target tissue.
Synthesis of Thyroid Hormone
Blood
Follicle Epithelium
Thyroid Peroxidase
I-
Na+
I-
Colloid
I2
Pump
TG
MIT+DIT
I2
+
T3
TG
DIT+DIT
MIT
+
Tyrosine
DIT
T3
+
T4
TG
-T3
-T4
-MIT
-DIT
TG
-T3
-T4
-MIT
-DIT
T4
Thyroid hormone synthesis and secretion involves processes that
occur within follicular epithelial cells and in colloid.
I-: iodide ions; I2: iodine; TG: thyroglobulin; MIT:
monoiodotyrosine; DIT: diiodotyrosine.
Synthesis of Thyroid Hormone
Tyrosine can be used for
neurotransmitters synthesis
Releases of Thyroid Hormone
• Stimulation of hormone secretion by TSH causes
the epithelial cells to engulf small globs of colloid
and move them into the cell by endocytosis.
Within the epithelial cell, MIT, DIT, T3, and T4 are
secreted into the blood while MIT and DIT are
broken down to I- and tyrosine molecules for
reuse by the epithelial cell.
• Most of the secreted T3 and T4 are carried in the
blood bound to thyroxinebinding globulin (TBG，).
T3 is more biologically active than T4, but since T4
synthesis occurs more rapidly, more T4 than T3 is
secreted. Target tissues contain an enzyme, 5’iodinase that converts T4 to T3.
Releases of Thyroid Hormone
Control of Thyroid Hormone
Secretion
• Secretion is stimulated by TSH, which
in turn is stimulated by TRH.
• TSH stimulates all aspects of thyroid
hormone synthesis and secretion and
also has a trophic effect.
• Elevated blood levels of T3 feed back
to the anterior pituitary thyrotrophs
and reduce TSH secretion.
Control of Thyroid Hormone Secretion
• TRH is release from the hypothalamus which acts on the anterior
pituitary thyrotrophs stimulating TSH release. TSH acts on the
thyroid gland stimulating every aspect of thyroid hormone synthesis
and secretion. TSH increase iodide uptake by follicular cells,
iodination of thyroglobulin, formation of MIT and DIT, and
endocytosis of colloid. These actions are mediated through G-protein
coupled membrane TSH receptors on the thyroid gland that stimulate
the formation of cyclic AMP and a cascade of protein phosphorylation
steps. With sustained TSH release, a trophic effect occurs causing
thyroid gland enlargement.
• T3 controls its own release through a negative feedback effect on the
pituitary thyrotrophs. Increasing blood levels of free T3 act on
pituitary thyrotrophs to decrease their number of TRH receptors. This
makes TRH less effective, decreasing the amount of TSH released and
therefore, the amount of thyroid hormone secreted. The net effect of
this feedback process is to produce a relatively constant blood level
of thyroid hormones.
Control of Thyroid Hormone Secretion
Hypothalamus
TRH
Anterior Pituitary
(Thyrotrophs)
(-)
TSH
Thyroid Gland
T3
Thyroid hormone (T3) limits its own secretion by inhibiting TSH
release from thyrotroph cells of the anterior pituitary.
Control of Thyroid Hormone Secretion
Action of Thyroid Hormones
• Because T3 acts by inducing DNA transcription, its effects on
tissue are the result of protein synthesis, primarily the
synthesis of enzymes (particularly the Na-K-ATPase involved
in ion transport).
• Thyroid hormones are required for normal growth throughout
life.
• Thyroid hormones affect basal metabolic rate (BMR, raises
the cellular oxygen consumption and heat production),
metabolism, the cardiovascular system (CO, Ventricular
contractility and HR↑), and the nervous system (excitability↑).
• Symptoms of thyroid hormone excess or deficiency can be
predicted from their normal effect (hyperthyroidism , an
autoimmune disease named Graves’ disease or
hypothyroidism, also an autoimmune destruction of the
thyroid gland, thyroiditis , maybe cretinism occur).
Hyperthyroidism
Hypothyroidism
Cretinism
ADRENAL GLAND
General Organization
• The adrenal gland, located above each kidney, is
divided into an outer cortex and an inner
medulla.
• The adrenal cortex secretes three classes of
steroid hormones－
mineralocorticoids,glucocorticoids
• and androgens－each form a different cell layer.
• The adrenal medulla secretes the
catecholamines, epinephrine, and
norepinephrine.
Anatomy of Adrenal Gland
Histology of Adrenal Gland
Adrenal Cortex
Hormone Synthesis
•Hormones of the cortex are all derived
from cholesterol (blood).
•Each cortical layer possesses unique
enzymes (P450 oxidases) that permit
the synthesis of layer-specific
hormones from the common precursor,
pregnenolone.
Hormone Synthesis of Adrenal Cortex
Hormone Synthesis of Adrenal Cortex
Zona Glomerulosa
Cholesterol→Pregnenolone→Progesterone→
11-Deoxycorticosterone→Corticosterone→Aldosterone
Stimulated by ACTH
Stimulated by
Angiotensin II & K+
Zona Fasciculata
Cholesterol→Pregnenolone→17-Hydroxypregnenolone→
17-Hydroxyprogesterone→11-Deoxycortisol→Cortisol
Stimulated by ACTH
Zona Reticularis
Cholesterol→Pregnenolone→
17-Hydroxypregnenolone→Dehyrdroepiandrostrone→Androstenedione
Each zone of the adrenal cortex utilizes different enzymes to synthesize specific
hormones from cholesterol. ACTH primarily stimulates secretions from the zona
fasciculata and reticularis while angiotensinⅡand K ions stimulate secretion
from the zona glomerulosa.
Control of Adrenal Cortex
hormone secretion
• Secretions of the zona fasciculata and reticularis are
under the sole control of the CRH-ACTH axis.
• Cortisol secretion from the zona fasciculata is
pulsatile with a diurnal rhythm driven by activity
within the brain.
• Stress stimulates the hypothalamus-pituitary-adrenal
axis to increase cortisol secretion.
• Cortisol secretion is limited by a negative feedback
system at the lever of both the hypothalamus and
anterior pituitary.
• Secretion of the zona glomerulosa are affected
primarily by the action of angiotensinⅡand to a lesser
extent by K ions and ACTH.
Control of Cortisol secretion
CRH
Anterior Pituitary (Corticotrophs)
ACTH
Adrenal Cortex (Zona Fasciculata)
(-)
N
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at
iv
e
F
e
e
d
b
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k
Hypothalamus
(-)
Cortisol
Cortisol limits its own secretion at the level of the hypothalamus
and anterior pituitary.
Control of Cortisol secretion
Circadian Rhythmic changes of
plasma cortisol concentration
Cortisol secretion is pulsatile with a diurnal variation driven by rhythmic neural activity in
the brain that stimulate pulsatile CRH release. Blood levels of cortisol are highest
immediately before waking and shortly thereafter. Stress and other stimuli override this
pattern by directly increasing CRH-ACTH-cortisol secretion.
Glucocorticoid Action
• Glucocorticoids (cortisol) are essential for life, and
without it, we cannot survive.
• It increases blood glucose levels (especially
during starvation, hypoglycemia, stress and
trauma), synthesis in the liver and reduces
glucose utilization by muscle and fat cells,
inhibiting insulin effect.
• Glucocorticoids are catabolic and diabetogenic,
reduce inflammation (PG↓, IL-2↓,His↓5-HT↓T-Cell↓),
suppress immune responses, and support vascular
response to catecholamines.
Glucocorticoid Action
Liver
Glucose Synthesis
Skeletal muscle
Glucose
Protein Breakdown
Amino Acids
Adipose Tissue
Fat Breakdown
Glycerol
Fatty Acids
Blood Levels
Glucose
Rise
Amino Acids
Rise
Fatty Acids
Rise
Cortisol elevates blood glucose levels by stimulating glucose synthesis
in the liver from amino acids and glycerol derived from protein and fat
breakdown, respectively.
Glucocorticoid Action
Androgen Action
• Adrenal androgens play an important role
in the female but not in the male Because
it do not contribute significantly to
testosterone synthesis.
• In the female, androgens are responsible
for the development of public and axillary
hair and for libido.
Pathology of Adrenal Cortex
• Abnormal adrenocortical secretion can
result from alterations in the gland
itself, the hypothalamus, or the
anterior pituitary.
• Abnormalities of the adrenal cortex
include Addison’s disease , Cushing’s
syndrome, and Conn’s syndrome.
• Abnormalities of the anterior pituitary
include Cushing’s disease.
Glucocorticoid and Clinic
In the hospital Exogenous
cortisol used for treatment
for long time cannot be
stopped at once!
Glucocorticoid and Clinic
Glucocorticoid and Clinic
Glucocorticoid and Clinic
Glucocorticoid and Clinic Addison’s Disease
Adrenocortical function deficiency
Pigment deposit
Addison’s disease usually results from an
autoimmune destruction of all three layers of
the adrenal cortex. The symptoms parallel the
loss of all adrenocortical hormones and
include hypoglycemia and weight loss due to
the absence of glucocorticoids as well as
increased plasma K and hypotension due to
the absence of aldosterone. In the absence of
adrenocortical hormones there is no negative
feedback inhibition of ACTH release, causing
blood ACTH levels to be very high. Because
MSH is a part of the ACTH molecule, the high
levels of ACTH cause the skin darkening of
patients with Addison’s disease.
Glucocorticoid and Clinic
Cushing’s Syndrome and Disease
Adrenocortical function overrun
“Full-moon” face
•Cushing’s syndrome is excess
production of glucocorticoids.
Some of the symptoms include
hyperglycemia, muscle wasting,
obesity, and hypertension. ACTH
levels will be low since there is
plenty of cortisol to inhibit its
release.
•Cushing’s disease results from
oversecretion of ACTH from a
pituitary tumor. What
distinguishes it from Cushing’s
syndrome is that the ACTH levels
are elevated. All other symptoms
are the same.
Glucocorticoid and Clinic Conn’s
Syndrome
Conn’s syndrome results from excess
aldosterone from an aldosteronesecreting tumor. Symptoms include
increase extracellular fluid volume,
hypertension, and reduced blood K
levels.
Adrenal Medulla
• The adrenal medulla is essentially a
neuroendocrine organ that is activated by
sympathetic preganglionic nerves.
• Nerve stimulation results in the release of stored
epinephrine (more) and norepinephrine (less) from
chromaffin cells (tyrosine).
• Catecholamines have widespread effects (through
β-adrenergic G-protein linked membrane receptors)
on the cardiovascular system, muscle system, and
metabolism (blood glucose levels↑).
PANCREAS
ENDOCRINE PANCREAS
General Organization
• Cells of the endocrine pancreas are organized into
clusters called islets of Langerhans.
• Islets of Langerhans are composed of three cell
types－alpha, beta, and delta—that secret
glucagons, insulin, and somatostatin, respectively.
• Blood flow from the beta cells carries insulin past
the alpha and delta cells and reduces their
secretion of glucagons and somatostatin,
receptively.
• Insulin and somatostatin inhibit, while glucagons
stimulates, the secretions of other islet cells.
HISTOLOGY OF PANCREAS
HISTOLOGY OF PANCREAS
Insulin
• Insulin is synthesized by β-cells from a
prohormone.
• Insulin is the hormone of plenty and is released
when metabolic supply (primarily glucose)
exceeds the needs of the body.
• Operating through tyrosine kinase receptors on
liver, skeletal muscle, and adipose cells, insulin
conserves glucose and increases fat storage and
protein synthesis.
• Insulin also helps maintain a low blood K ion level
by stimulating the Na-K-ATPase pump.
Synthesis of Insulin
Insulin is synthesized from an 86 amino acid prohormone by
enzymatically removing a central amino acid string and linking the
remaining strands with two disulfide bonds. The final hormone looks
like two railroad tracks (amino acid chains) held together by two
ties (disulfide bonds). This synthesis occurs within storage vesicles
of the β-cells.
Secretion of Insulin
• In response to a meal, insulin secretion is stimulated. An elevated
blood glucose level is the primary stimulus for insulin secretion.
Glucose binds to its glut 2-transporter on pancreatic β-cells, which
carries it into the cell by facilitated transport. Inside the cell, glucose
metabolism leads to increase ATP levels, which in turn open Kchannels depolarizing the cell and increasing intracellular calcium
concentration. Elevated Ca induces fusion of the storage vesicles with
the cell membrane and stimulates insulin release. Fatty acids and
amino acids also stimulate insulin secretion, presumably through a
similar mechanism. Glucagon stimulates insulin secretion by acting
directly through a G- protein linked receptor on β-cells as well as
indirectly by elevating blood glucose levels (see next section). On the
other hand, somatostatin inhibits insulin secretion by acting directly
on the β-cells and indirectly by reducing the ability of glucagon to
stimulate insulin secretion.
Function of Insulin
Liver
Glucose Stored as Glycogen
Skeletal muscle
Protein Synthesis
Amino Acids
Adipose Tissue
Glucose
Fat Synthesis
Fatty Acids
Blood Levels
Glucose
Fall
Amino Acids
Fall
Fatty Acids
Fall
Blood K ion
Fall
Insulin reduces blood glucose levels by stimulating glucose uptake into
muscle
and
fat
as
well
as
by
inhibiting
the
formation
(gluconeogenesis) and release of glucose by the liver.
Function of Insulin
Function of Insulin
Mechanism of Insulin
Mechanism of Insulin
Mechanism of Insulin
Glucagon
• Glucagon is a single chain of 29 amino acids
synthesized by α-cells.
• Glucagon acts primarily on the liver to increase and
maintain blood glucose levels.
• Glucagons secretion is increased in response to falling
blood glucose and increasing blood amino acid levels.
• Glucagon secretion is inhibited by insulin acting
directly on α-cell through the insulin-receptor.
• Glucagon restores blood glucose levels by stimulating
glucose synthesis from amino acids and by stimulating
fat metabolism.
• Secretion rates of glucagons and insulin change in
opposite directions to maintain blood glucose
homeostasis.
Function of Glucagon
Liver
Glucose Synthesis & Fatty Acid
Metabolism
Glucose
Adipose Tissue
Fat Breakdown
Amino Acids
Fatty Acids
Blood Levels
Glucose
Rise
Amino Acids
Rise
Glucagon elevates blood glucose levels by stimulating the synthesis of
new glucose by the liver from amino acids (gluconeogenesis). In
addition, glucagon stimulates the liver to metabolize fatty acids rather
than glucose.
Interaction between insulin and glucagon
Glucagon and insulin work together to guard against
hypoglycemia (glucagon) and hyperglycemia (insulin). Glucagons
stimulates breakdown (catabolism) of fats and proteins so that
fatty acids can be used for fuel and amino acids can be converted
to glucose (gluconeogenesis) thereby guarding against a fall in
blood glucose levels. On the other hand, insulin stimulates
glucose uptake from the blood and its conversion to fats and
glycogen thereby guarding against excess blood glucose. To
maintain this balance, blood levels of glucagon and insulin exhibit
a reciprocal relationship with the blood glucose level determining
the balance. In the fed state, insulin levels are high compared to
glucagons levels because the high blood glucose stimulates
insulin secretion. In addition, the high insulin levels would inhibit
glucagon release. However, as blood glucose levels fall during an
overnight or a prolonged fast, glucagons secretion increases and
insulin secretion decreases so that glucagons levels exceed
insulin levels.
Interaction between insulin and glucagon
Interaction between insulin and glucagon
Interaction between insulin and glucagon
Somatostatin
• Somatostatin is a peptide hormone
released from δ-cells.
• Somatostatin acts in a paracrine
manner to inhibit glucagon and
insulin secretion locally.
• Somatostatin secretion is increased in
response to a meal and, therefore,
acts to modulate the response of
insulin and glucagon to a meal.
Diabetes Mellitus
• Diabetes mellitus is a disease of altered insulin function and
is in two forms.
• Type I is primarily due to the inability of β-cells to produce
and secrete insulin (autoimmune reaction); type Ⅱ is
characterized by marked resistance of target tissues to
insulin (obesity, aging, various illnesses).
• Metabolic characteristics consist of elevated blood glucose
levels, elevated blood amino acid levels, and elevated free
fatty acids leading to formation of ketone bodies and
acidemia.
• Blood level of K ions is also elevated.
• Elevated blood glucose levels lead to osmotic diuresis
(dehydration, polyuria, thirst ).
• Chronic complications of this metabolic disorder affect the
eyes, the kidneys, the peripheral nervous system, and the
vascular system.
Blood concentration changes in
glucagon, insulin and glucose
Diabetes Mellitus
Examination of diabetes Mellitus
Mechanism of Diabetes Mellitus
Relationship between the blood
glucose and various hormones
Neuropeptide，
Structure of Bone
Histology of Bone
Histology of Bone
CALCIUM AND PHOSPHATE
REGULATION
General Consideration
• Approximately half of the calcium in the blood is ionized, the
biologically active form.
• Approximately half of the calcium in the blood is bound to
albumin or is complexed with anions such as phosphates and
sulfates.
• Blood Ca homeostasis produced through the interaction of bones,
kidneys, and small intestine.
• Parathyroid hormone, calcitonin, and vitamin D are the three
hormones of Ca homeostasis.
• Hypercalcemia (depress nerve excitability) is characterized by
constipation, polyuria, and lethargy; hypocalcemia (increase
nerve excitability) is characterized by spontaneous muscle
twitching, cramps, tingling, and numbness.
Parathyroid Gland
• Parathyroid gland senses blood Ca
levels through cell surface receptors.
• Parathyroid gland secretes PTH (84
amino acids) in response to reduced
blood Ca levels (by cAmp-induced
mechanism).
• PTH stimulates (1) bones dissolution,
(2) renal Ca reabsorption, and (3)
intestinal Ca absorption.
Function of Parathyroid Hormone
Vitamin D
• Vitamin D (cholecalciferol) is a steroid obtained
from the diet or synthesized by the skin (from
cholesterol under the effect of ultraviolet light).
• Active form of vitamin D (1,25
dihydroxycholecalciferol) is formed in the
kidneys through the action of 1α-hydroxylase.
• Activity of 1α-hydroxylase is influenced by the
blood levels of Ca and PTH.
• Vitamin D elevates blood levels of both Ca and
phosphate (from DNA levels) through actions
on the small intestines, kidneys, and bone.
Function of Vitamin D
Calcitonin
• Calcitonin (32 amino acids) is
synthesized by parafollicular cells or C
cells of the thyroid gland.
• Increased blood Ca levels stimulate
calcitonin secretion.
• Calcitonin inhibits osteoclast bone
resorption reducing blood Ca levels.
• Its physiological function is not well
defined.
Function of parathyroid hormone
and calcitonin (summary)