XIII Endocrinology

by He Wei
Department of Physiology
Zhengzhou University
What is hormone?

Chemical substances that are produced in the

endocrine glands and traveled in the blood to
target cells or organs where they exert the
physiological control.
A given hormone usually affects only a limited
number of cells, which are called target cells. A
target cell responds to a hormone because it
bears receptors for that hormone.
 imp
Two important terms are used to refer to
molecules that bind to the hormone-
binding sites of receptors:

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 sites of the agonist, but fail to
trigger intracellular signaling events.
What is endocrine system?
A system of glands that works with the
nervous system in controlling the activity
of internal organs, and in coordinating the
long-range response to external stimuli.
Endocrine Gland and Exocrine Gland
Hormones groups

 Steroids: testosterone 、 estradiol 、 adrenal

cortex hormones

 Peptides: most hormones

 Amines: thyroid hormone 、

norepinephrine 、 epinephrine
Mechanisms of Hormonal Action

imp
 By activating the cyclic AMP system of the cells, which in
turn activates multiple other intracellular functions.
 By activating the genes of the cell, which causes the
formation of intracellular proteins that in turn initiate
specific cellular function.
The Cyclic AMP Mechanism for Controlling Cell
Function----A “Second Messenger” for
Hormone Mediation

Nonsteroid hormones (water soluble) do not

enter the cell but bind to plasma membrane
receptors, generating a chemical signal
(second messenger) inside the target cell.
Second messengers activate other intracellular
chemicals to produce the target cell response.
 The specific action that occurs in response
to cAMP in each type of target cell depends
upon the nature of the intracellular machinery.
Different functions are elicited in different
target cells ------ such functions as:

 Initiating synthesis of specific intracellular

chemicals;
 causing muscle contraction or relaxation;
 initiating secretion by the cells;
 altering the cell permeability;
 and many other possible effects.
cascade of enzymes
 Action of Steroid Hormones on the Genes to
Cause Protein Synthesis

 The steroid hormones enters the cytoplasm of the cell, where it

binds with a specific receptor protein to form a hormone-receptor
complex.
 The complex is transported into the nucleus.
 The complex then actives specific genes to produce mRNA.
 The mRNA diffuses into the cytoplasm, where it promotes the
translation process at the ribosomes to produce new proteins.
 Control of Endocrine Activity

The concentration of hormone as seen by

target cells is determined by three factors:

 Rate of production

 Rate of delivery

 Rate of degradation and elimination

 Feedback Control of Hormone
Production

Feedback circuits are at the root of most

control mechanisms in physiology, and are
particularly prominent in the endocrine system.
Instances of positive feedback certainly occur,
but negative feedback is much more common.
 Neurons in the hypothalamus
secrete thyroid releasing hormone
(TRH), which stimulates cells in
the anterior pituitary to secrete
thyroid-stimulating hormone
(TSH).

 TSH binds to receptors on

epithelial cells in the thyroid gland,
stimulating synthesis and
secretion of thyroid hormones,
which affect probably all cells in
the body.

 When blood concentrations of

thyroid hormones increase above
a certain threshold, TRH-secreting
neurons in the hypothalamus are
inhibited and stop secreting TRH.
This is an example of "negative
feedback".
The Pituitary Gland, Its Multiple
Control Functions, and Its
Relationship to The
Hypothalamus
 The pituitary gland (often called the master
gland) is located in a small bony cavity at the
base of the brain. A stalk links the pituitary to
the hypothalamus, which controls release of
pituitary hormones. The pituitary gland has two
lobes: the anterior lobe and posterior lobe. The
anterior pituitary is glandular.
 The hypothalamus contains neurons that
control releases from the anterior pituitary.
Hypothalamic hormones are released into a
portal system connecting the hypothalamus
and pituitary, and cause targets in the pituitary
to release hormones.
 Growth Hormone
Growth hormone, also known as
somatotropin, is a protein hormone of 191
amino acids that is synthesized and
secreted by cells called somatotrophs in the
anterior pituitary. It is a major participant in
control of several complex physiologic
processes, including growth and
metabolism.
Metabolic Effects (Direct )
 Increased rate of protein synthesis in all
cells of body;
 Increased mobilization of fatty acids from
adipose tissue, and increased use of the
fatty acids for energy;
 Decreased rate of glucose utilization
throughout the body.
Growth Effects (Indirect)
Growth is a very complex process, and
requires the coordinated action of several
hormones. The major role of growth
hormone in stimulating body growth is to
stimulate the liver and other tissues to
secrete several small proteins called
somatomedins, which stimulates
proliferation of cartilage cells, resulting in
bone growth.
Regulation of GH Secretion

 Starvation, hypoglycemia, exercise,

excitement, trauma;
 Stress status;
 Growth hormone-releasing hormone (GHRH)
from hypothalamus;
 Sleep
Abnormalities of GH Secretion

 Dwarfism

 Giantism

 Acromegaly
 Age: 22
 Sex: male
 Height: 75cm
 Weight: 12.5kg
 Thyroid Hormones
 The thyroid gland is a very vascular and
butterfly shaped gland that is located in the
neck.
 The thyroid gland secretes three hormones:
thyroxine(T4), triiodothyronine(T3), and
calcitonin(detailed latter).
 Both of T3 and T4 require iodine for their
synthesis and have a profound effect on the
metabolic rate of body.
Thyroid follicles serve
as both factory and
warehouse for thyroid
hormones.
Formation and Secretion of the
Thyroid Hormones

 Accumulation of the raw materials

 Synthesis of the hormones and storage

 Release of the free hormones and

secretion into blood
Two Principle Raw Materials

 Tyrosine is provided from a large glycoprotein

called thyroglobulin, which is synthesized by
thyroid epithelial cells and secreted into the
lumen of the follicle .
 Iodine, or more accurately iodide (I-), is avidly
taken up from blood by thyroid epithelial cells,
which have “iodide pumps” on their membrane.
Iodination of Tyrosine and Formation
of the Thyroid Hormones

 Iodination of tyrosines on thyroglobulin and

formation of monoiodotyrosine and
diiodotyrosine

 Synthesis of T4(di+di) or T3(mono+di)

Release of T4 and T3 from the Thyroid
Gland

 Thyroid epithelial cells ingest colloid by endocytosis from

their apical borders - that colloid contains thyroglobulin
decorated with thyroid hormone.

 Colloid-laden endosomes fuse with lysosomes, which contain

hydrolytic enzymes that digest thyroglobluin, thereby
liberating free thyroid hormones.

 Finally, free thyroid hormones diffuse out of lysosomes,

through the basal plasma membrane of the cell, and into
blood where they quickly bind to carrier proteins for transport
to target cells.
 Functions of the Thyroid
Hormones

It is likely that all cells in the body are

targets for thyroid hormones. While not
strictly necessary for life, thyroid hormones
have profound effects on many "big time"
physiologic processes, such as
development, growth and metabolism.
Effect of Thyroid Hormone on Cellular
Metabolic Activity

The thyroid hormones increase the

metabolic activities of all or almost all the
tissues of the body. The basal metabolic
rate can increase to as much as 60 to 100
per cent above normal when large
quantities the hormones are secreted. The
rate of utilization of foods for energy is
greatly accelerated .
Effect of Thyroid Hormone on Development
and Growth

 Stimulation of skeletal growth in childhood.

In those who are hypothyroid, the rate of
growth is greatly retarded.

 Promotion of normal brain development in

the early postnatal period. Those who are
hypothyroid will remain mentally deficient
throughout life.
 Metabolic Effects

 Elevation of basal metabolic rate with increased O2

consumption and heat production;
 Stimulation of carbohydrate metabolism with increases
in gastrointestinal and cellular absorption of glucose,
glycolysis and gluconeogenesis;
 Stimulation fat mobilization, leading to increased
concentrations of fatty acids in plasma. Increased
oxidation of fatty acids in many tissues.
 Increased protein synthesis and breakdown.
Systemic Effects

 Cardiovascular system: Thyroid hormones

increases heart rate, cardiac contractility and
cardiac output. They also promote vasodilation,
which leads to enhanced blood flow to many organs
to fit for the increased need for O2 and nutrition by
them.
 Central nervous system: Individual with too little
thyroid hormone tends to feel mentally sluggish,
while too much induces anxiety and nervousness.
 Respiration system: Increased rate and depth of
respiration. WHY?
 Gastrointestinal tract: In addition to increased
appetite and food intake, thyroid hormone
increases gastrointestinal motility and secretion.
 Body weight: Greatly increased thyroid hormone
always decreases the body weight.
 Sleep: Because of the excitable effects of thyroid
hormone, it is difficult to sleep.
 Eyes: Many, but not all persons with
hyperthyroidism develop protrusion of the
eyeballs.
Patient with exophthalmic hyperthyroidism
Regulation of TH Secretion

Hypothalamus--Anterior Pituitary--Thyroid gland

(TRH) (TSH) (TH)

Negative feedback
 Calcitonin

This hormone is secreted by the C cells of

the thyroid gland. It participates in calcium
and phosphorus metabolism.
Physiologic Effects of Calcitonin

 Bone: Calcitonin inhibits the activity of osteoclasts, a cell

type that "digests" bone matrix, releasing calcium and
phosphorus into blood.

 Kidney: Calcium and phosphorus are prevented from

being lost in urine by reabsorption in the kidney tubules.
Calcitonin inhibits tubular reabsorption of these two ions,
leading to increased rates of their loss in urine.
Control of Calcitonin Secretion

The most prominent factor controlling

calcitonin secretion is the plasma
concentration of Ca2+. Elevated blood calcium
levels strongly stimulate calcitonin secretion,
and secretion is suppressed when calcium
concentration falls below normal.
 Parathyroid Hormone

 Parathyroid hormone is the most important

endocrine regulator of calcium and
phosphorus concentration in extracellular
fluid.
 This hormone is secreted from cells of the
parathyroid glands and finds its major target
cells in bone and kidney.
Physiologic Effects of Parathyroid Hormone

 Mobilization of calcium from bone: Although the

mechanisms remain obscure, a well-documented effect of
parathyroid hormone is to stimulate the activity of
osteoclasts, liberating calcium into blood.

 Enhancing absorption of calcium from the small

intestine: Facilitating calcium absorption from the small
intestine would clearly serve to elevate blood levels of
calcium. Parathyroid hormone stimulates this process, but
indirectly by stimulating production of the active form of
vitamin D in the kidney. Vitamin D induces synthesis of a
calcium-binding protein in intestinal epithelial cells that
facilitates efficient absorption of calcium into blood.
 Suppression of calcium loss in urine: In addition to
stimulating fluxes of calcium into blood from bone and intestine,
parathyroid hormone puts a brake on excretion of calcium in
urine, thus conserving calcium in blood. This effect is mediated
by stimulating tubular reabsorption of calcium. Another effect of
parathyroid hormone on the kidney is to stimulate loss of
phosphate ions in urine.
Control of Parathyroid Hormone Secretion

 Parathyroid hormone is released in response to

low extracellular concentrations of free calcium.
 Changes in blood phosphate concentration can
be associated with changes in parathyroid
hormone secretion, but this appears to be an
indirect effect and phosphate is not a significant
regulator of this hormone.
The Adrenocortical Hormones
 The adrenal produces three major
classes of hormones, each of which aid in
dealing with the multitude of small and large
stresses faced by animals and people
almost daily. There is no doubt that at least
two of these groups - glucocorticoids and
mineralocorticoids - are necessary for life.
 Mineralocorticoid
--Aldosterone
Removal of the adrenal glands leads to
death within just a few days. Observation of
such a unfortunate subject would reveal several
key derangements:
 the concentration of potassium in extracelluar fluid
becomes dramatically elevated
 urinary excretion of sodium is high and the
concentration of sodium in extracellular fluid
decreases significantly
 volume of extracellular fluid and blood decrease
 the heart begins to function poorly, cardiac output
declines and shock ensues
Physiologic Effects of Aldosterone

 Increased resorption of sodium: sodium loss in urine

is decreased under aldosterone stimulation.

 Increased resorption of water, with consequent

expansion of extracellular fluid volume. This is an
osmotic effect directly related to increased resorption of
sodium.

 Increased renal excretion of potassium.

Control of Aldosterone Secretion

 Concentrations of K+ and Na+ in extracellular fluid:

Small increase of K+ and decrease of Na+ in blood levels
strongly stimulate aldosterone secretion.

 Angiotensin II: Activation of the renin-angiotensin

system as a result of decreased renal blood flow
(usually due to decreased vascular volume) results in
release of angiotensin II, which stimulates aldosterone
secretion.
 Glucocorticoid
---Cortisol

In contrast to loss of mineralocorticoids,

failure to produce glucocorticoids is not
acutely life-threatening. Nevertheless, loss
or profound diminishment of glucocorticoid
secretion leads to a state of deranged
metabolism and an inability to deal with
stressors which, if untreated, is fatal.
Effects on Metabolism

The name glucocorticoid derives from early

observations that these hormones were
involved in glucose metabolism. In the
fasted state, cortisol stimulates several
processes that collectively serve to
increase and maintain normal
concentrations of glucose in blood.
These effects include:
 Stimulation of gluconeogenesis, particularly in the liver:
This pathway results in the synthesis of glucose from non-
hexose substrates such as amino acids and lipids and is
particularly important in carnivores and certain herbivores.
Enhancing the expression of enzymes involved in
gluconeogenesis is probably the best known metabolic function
of glucocorticoids.
 Mobilization of amino acids from extrahepatic tissues:
These serve as substrates for gluconeogenesis.
 Inhibition of glucose uptake in muscle and adipose tissue:
A mechanism to conserve glucose.
 Stimulation of fat breakdown in adipose tissue: The fatty
acids released by lipolysis are used for production of energy in
tissues like muscle, and the released glycerol provide another
substrate for gluconeogenesis.
 Stress Resistance

The increased Cortisol levels stimulated by stressful

conditions, such as trauma, starvation, infection,
intense heat or cold, surgery, debilitating disease.
 Availability of glucose: Cortisol promotes a rapid
supply of glucose to the body tissues through its
metabolic effects.
 Cardiovascular effects: Cortisol plays a permissive
role in the cardiovascular responses to stress through
increased sympathetic activity. This causes vascular
construction, which helps to maintain arterial pressure
and directs blood towards the most vital organs.
Effects on Inflammation and
Immune Function
Glucocorticoids have potent anti-
inflammatory and immunosuppressive
properties. Cortisol inhibits lymphocyte
activation and as a consequence, it is
widely used as drugs to treat inflammatory
conditions such as arthritis or dermatitis,
and as adjunction therapy for conditions
such as autoimmune diseases.
 Control of Cortisol Secretion

 Hypothalamus--Anterior Pituitary--Adrenal gland

(CRH) (ACTH) (Cortisol)

 Stress