Efectele hormonilor

Table 17.4 pt 1

Table 17.4 pt 2

Table 17.5

Growth Hormone
Targets liver to produce somatomedins
mitosis + cellular differentiation for tissue
growth
protein synthesis
mRNA translated, DNA transciption for mRNA
production
enhances amino acid transport into cells, catabolism

lipid metabolism
stimulates FFA and glycerol release, protein sparing

CHO metabolism
glucose sparing effect- glucose stored as glycogen

Electrolyte balance
promotes Na+, K+, Cl- retention, Ca+2 absorption

Growth Hormone 2
Childhood
bone, cartilage and muscle growth

Adulthood
osteoblastic activity, appositional growth affecting
bone thickening and remodeling

Levels of GH
higher during first 2 hours of deep sleep, after high
protein meals, after vigorous exercise
lower after high CHO meals
decline with age

EFFECTS OF VASOPRESSIN AND OXYTOCIN

Vasopressin has two important actions, and each

of its two names indicates one of them. The first
target tissue is the kidney. In a certain part of the
nephron water reabsorption depends on
vasopressin, so that in its absence this section is
impermeable to water. The drive for this water
reabsorption is an osmotic gradient: the
concentration of NaCl in the extracellular fluid in
that part of the kidney is much higher than in the
lumen of the nephron. This is the antidiuretic
effect of vasopressin.
The action of vasopressin in the kidney is
mediated by the V2 receptors, which are coupled
to activation of adenylate cyclase and elevation of
cAMP.

The second effect of vasopressin is the

constriction of visceral blood vessels. This effect
is mediated by receptors of type V1, located in the
smooth muscle of these blood vessels. V1
receptors activate PI-PLC , and thus cause an
increase in cytosolic calcium ions.
Oxytocin also has two important effects. The first
one is stimulation of uterine contraction. Oxytocin
activates its receptors in the uterine smooth
muscle (myometrium), which are coupled to the
activation of PI-PLC .
The other effect of oxytocin is stimulation of milk
ejection from the mammary glands under the
stimulus of suckling. This effect is also mediated
by activation of PI-PLC .

Table 17.7

EFFECTS OF THYROID HORMONES

Thyroid hormones affect virtually all cell types.
The mode of action of thyroid hormones is
described in the presentation on Nuclear
Receptors.
The half-life of T4 and T3 is 7 days and one day,
respectively. These half-lives are extremely long
compared to other hormones.
The first group of actions of thyroid hormones
includes effects of development and growth. Only
some of them are adequately undestood.
Very prominent in importance is the requirement
of thyroid hormones for the development of the
neural system. This refers to the fetus as well as
to the child.

In the developed countries, including Israel,

thyroid hormones are measured in every newborn.
In cases of deficiency (thyroid malformation, or
the rare cases of mutations in essential thyroid
genes), replacement started immediately after
birth normalizes (or almost normalizes) child
development.
Replacement means T4 taken orally (as is the case
in hypothyroidism which develops in adulthood).
Thyroid hormones also play an important role in
children growth.
Growth hormone (GH), a protein hormone
produced in the anterior pituitary (cell type:
somatotroph), acts to stimulate growth in children.

The activated receptor of thyroid hormones is one

of the transcription factors required for the
expression of growth hormone. Thus
hypothyroidism in children impairs growth.
Most of the effects of the thyroid hormones are
related to increasing the rate of body metabolism.
One of the most important functions of thyroid
hormones is the maintenance of body temperature.
In severe hypothyroidism body temperature goes
down drastically, which is a life-threatening
condition.
The main mechanism for increasing body
temperature is accelerating the rate of oxidative
processes cells.

Among the effects of thyroid hormones, a major

group is due to increased expression of type
adrenergic receptors (ARs). This results in
enhancement of the effects of epinephrine and
norepinephrine via receptors (see the
presentation on the adrenal medulla).
Increased expression of AR1 in the heart results
in increased heart rate and increased force of
heart muscle contraction. This increases energy
utilization by the heart.
An increase in the same receptors in adipose
tissue results in increased lipolysis.
Increased expression of AR2 in liver and skeletal
muscle stimulates glycogenolysis and inhibits
glycogen synthesis.

All the processes described above, plus a few

others accelerated by thyroid hormones, result in
increased rates of ATP utilization, ATP (and heat)
production, and the supply of substrates for
oxidation.
All these contribute to a parameter called basal
metabolic rate (BMR), which is determined by
oxygen consumption when the animal is at rest.
Thyroid hormones were found to increase BMR
many years ago, before many of the mechanisms
involved were recognized.
Thyroid hormones increase alertness, rapidity of
responses, and nervousness. This is also a result
of their augmentation of adrenergic receptor
expression.

CALCITONIN
Outside the follicular structure, cells of a different
type can be observed: these are the C-cells which
produce the hormone calcitonin.
Calcitonin acts to decrease the concentration of
calcium ions in the blood, and is relatively less
important than other hormones which affect
calcium metabolism in the body: parathyroid
hormone (PTH) and vitamin D.
Parathyroid hormone is produced by four tiny
glands, the parathyroid glands, which are attached
on the outside of the thyroid. However, they are
functionally independent of the thyroid and are
independently regulated

EFFECTS OF ACTH ON THE CORTISOL-PRODUCING

CELLS

ACTH activates adenylate cyclase, and its action

are mediated by cAMP.
ACTH can stimulate cortisol production within
minutes. This effect is due to the phosphorylation
(via PKA) of StAR (steroidogenic acute regulatory
protein). Activated StAR stimulates the transport
of cholesterol across the mitochondrial inner
membrane, to the matrix. The Matrix is the
location of the first enzyme in steroidogenesis, the
cholesterol side-chain cleavage enzyme (P450scc).
This reaction is rate-limiting in steroidogenesis,
but substrate availability, rather than the intrinsic
enzyme activity, is the limiting factor.

ACTH also have slower stimulatory effects on the

adrenal cortisol-producing cells. These are due to
increased transcription of genes required for
cortisol synthesis. They include StAR, as well as
all the steroidogenic enzymes which participate in
cortisol production. As a result of these actions
these adrenal cells increase in size (a hypertrophic
effect).
ACTH also stimulates proliferation of the cortisolproducing cells (a hyperplastic effect).
Thus, prolonged exposure to large amounts of
ACTH (as in chronic illness) results in abnormally
large adrenals.

EFFECTS OF CORTISOL
Cortisol has many target cells and many effects.
Most of the effects are related to the need to cope
with long-term stress. This includes actions
aimed at keeping normal glucose levels in the face
of food deprivation. This is often associated with
the animal being wounded or ill, situations in
which the immune system is stimulated. Many
effects of cortisol result in restraining (inhibiting)
the immune system, since too extensive immune
responses can be life-threatening. Another stress
situation which can benefit from cortisol actions is
prolonged extensive physical effort.

METABOLIC EFFECTS OF CORTISOL

In the liver, cortisol stimulates gluconeogenesis
(production of glucose from non-sugar
compounds: amino acids, glycerol, lactate) . See
the presentation on the adrenal medulla for details
on the biochemistry of gluconeogenesis.
At the same time, cortisol acts on many other
tissues to shift their metabolic balance to
catabolism rather than anabolism, thus making
them suppliers of precursors for gluconeogenesis.
Cortisol has nuclear receptors (the glucocorticoid
receptor) and its effects are mediated by
activation of this receptor (see the presentation on
nuclear receptor).

Cortisol has catabolic effects in skeletal muscle,

connective tissue, bone, skin, adipose tissue, and
other tissues.
These catabolic effects are of course damaging,
but the top priority of the body is supplying
glucose to the brain, which is rapidly and
irreversibly damaged by glucose shortage. Red
blood cells (erythrocytes) also require glucose
exclusively).
In the peripheral tissues mentioned above, cortisol
inhibits glucose uptake, and in skeletal muscle it
also inhibits amino acid uptake.
In each of these tissues cortisol inhibits the
transcription of specific genes expressed in that
tissue. The inhibited genes usually code for
proteins which are produced in large amounts.

In some tissues cortisol may also stimulate

protein degradation.
In adipose tissue cortisol increases lipolysis by
supporting the lipolytic action of epinephrine.
This supplies fatty acids for tissues which can use
them as well as glycerol for gluconeogenesis.
In children, cortisol inhibits growth by inhibiting
the epiphyses. The epiphyses are strips of
proliferating cells, found near the edges of long
bones. These cells eventually differentiate to bone
cells. Steroid sex hormones, which go up at
adolescence, cause epiphysis closure
(disappearance). Cortisol just inhibits epiphyseal
cell proliferation reversibly.

In the liver, cortisol stimulates gluconeogenesis in

several ways. It increases amino acid transport
into the liver, which is the main site of amino acid
metabolism. This results in most cases in the
formation of pyruvate or oxaloacetate, which are
substrates for gluconeogenesis.
A major effect of cortisol is stimulation of the
expression of two gluconeogenic enzymes:
glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (PEPCK).
Cortisol, paradoxically, stimulates the activity of
glycogen synthase. However, glycogen synthase
requires glucose-6-phosphate as an allosteric
activator. Thus, glycogen is synthesized only if
excessive glucose is transiently found in the liver.

EFFECTS OF CORTISOL ON THE IMMUNE SYSTEM

All cell types of the immune system have
glucocorticoid receptors, and in each cell type
cortisol inhibits the specific functions of this
particular cell.
Cortisol inhibits the expression of dozens of genes
encoding cytokines and various hydrolytic
enzymes, acting either directly on their genes or
indirectly. Cortisol inhibits the synthesis of
eicosanoids (prostaglandins, thromboxane,
leukotrienes). These compounds are all
derivatives of the polyunsaturated fatty acid
arachidonic acid. They act as local regulators via
membranal receptors coupled to heterotrimeric Gproteins.

Eicosanoids play an important role in processes of

inflammation and allergy, including pain. Drugs
like aspirin, ibuprofen (nurofen, advil), and acamol
inhibit the production of some eicosanoids.
Most of the immunosuppressive effects of cortisol
are exerted by binding to, and neutralizing the
activity of, some transcription factors, which play
a key role in the immune response (e.g., NF- B,
AP-1 or Jun.Fos).
However, some of the immunosuppressive effects
are mediated by stimulating the expression of
genes, where a glucocorticoid receptor (GR)
homodimer binds directly to the DNA.

Most, if not all, of the metabolic effects of cortisol

(see above) are mediated by direct binding of GR
homodimer to the DNA in the relevant promoters.
Numerous structural anlogs of cortisol are used in
clinical medicine for the suppression of the
immune response. Unfortunately, these synthetic
glucocorticoids have all the effects mediated by
the glucocorticoid receptor, including the
catabolic ones. These drugs have a half-life
longer than that of cortisol.
To some extent, cortisol can activate the
mineralocorticoid receptor, thus mimicking the
action of aldosterone. However, the synthetic
glucocorticoids are almost free of such activity.

Renin

Converts angiotensinogen to angiotensin I

Angiotensin I is converted to angiotensin II

Angiotensin II

1. Stimulates adrenal

2.
3.
4.

production of
aldosterone
Stimulates pituitary
release of ADH
Promotes thirst
Elevates blood
pressure

Heart

Produces natriuretic peptides (ANP and BNP):

when blood volume becomes excessive

Natriuretic Peptide

Action opposes angiotensin II

Resulting in reduction in blood volume and
blood pressure

Thymus

Produces thymosin hormones:

that helps develop and maintain normal immune
defenses

Testes

Produce androgens in interstitial cells:

testosterone

Secrete inhibin in sustentacular cells:

support differentiation & physical maturation of
sperm

Ovaries

Produce estrogens
After ovulation, follicle cells:

reorganize into corpus luteum

release estrogens & progestins, especially progesterone

Adipose Tissue Secretions

1. Leptin:
feedback control for appetite
controls normal levels of GnRH, gonadotropin
synthesis
2. Resistin: reduces insulin sensitivity

Endocrine Functions of Other

Organs
Heart - atrial natriuretic factor
blood volume + BP, from Na+ and H2O loss by
kidneys

Kidneys
calcitriol - Ca+2 and phosphate: absorption, loss for
bone deposition
erythropoietin - stimulates bone marrow to produce
RBCs

Stomach and small intestines - enteric hormones

coordinate digestive motility and secretion

Endocrine Functions of Other

Organs 2
Liver
angiotensinogen (a prohormone)
precursor of angiotensin II, a vasoconstrictor

erythropoietin (15%)
somatomedins - mediate action of GH

Placenta
secretes estrogen, progesterone and others
regulate pregnancy, stimulate development of fetus
and mammary glands