Endocrinology

 It is one of the body’s two (2) major communication systems.
 A system in which a group of secretor cells (a gland) secretes a
potent chemical transmitter substance which is known as a
hormone, into the BLOOD. The transmitter is then carried by the
blood to the target cells where a response is elicited
 Differs from the other systems.
 The activity of the endocrine system complements that of the
nervous system
-the nervous system involves rapid short lived communication
between Individual cells
-the endocrine system involves slower prolonged communication
between large numbers of cells.
 The endocrine system is essential for maintenance of
homeostasis.

 Some organs in the endocrine systems are
involved in and have numerous functions in
other systems
 A single gland may secrete multiple
hormones, reflecting different types of
endocrine cells in the same gland.
 In a few cases a single cell may secrete more
than one hormone (E.g. Anterior Pituitary –
follicle stimulating hormone and luteinizing
hormone).
 A particular hormone may be produced by
numerous endocrine glands

 A chemical messenger secreted by an
endocrine gland cell is often also secreted by
other types of cells and serves in these
locations as a
 -neurotransmitter
 - paracrine
 -autocrine

 The endocrine system is contains 6 major
glands including many others.

 A hormone is chemical message transmitted
in the BLOOD that is secreted by an endocrine
gland.
 Hormones can be classified into three(3)
categories
 -Amines
 -Peptides and Proteins
 -Steroids.

 Proteins that act as hormones.
 Size of the polypeptide varies from 3 to 200
amino acid residues.
 Cannot pass through cell membranes due to
their size and water soluble nature.
 Protein hormones are the most numerous
types.
 Secreted by many glands

 Polypeptide hormones synthesized in the same
manner as any other protein.
 DNA in the nucleus is transcribed to mRNA and
translated into the protein by ribosomes
 Protein is then processed by the golgi apparatus and
stored in the secretory granules.
 Many hormones undergo changes in the golgi
apparatus/secretory granules
-Cleavage reactions
-Addition of carbohydrate groups.

 Secretory Granules released by exocytosis.
 This occurs when the membrane of the
granule fuses with the membrane of the cell
causing the contents to be ejected.
 The process is triggered by calcium entering
the cell.
 Polypetide hormone release is controlled
mainly by regulating secretion rather than
synthesis.

 Small and fat soluble
 Can pass through cell membranes but they
must circulate bound to plasma proteins
since they
 Are insoluble in blood.
 Secreted by certain glands.

 Derived from cholesterol.
 Cholesterol is acquired from the diet or
synthesized within cells
 All steroids have the have the same basic
structure formed by four(4) rings of carbon.
 Individual steroid hormones differ primarily .

Cholesterol Pregnenolone Progesterone
•Testosterone
•Oestrogens eg.oestradiol
Androgens
•Cortisol
Glucocorticoids
•Aldosterone.
Mineralcorticoids

 Released immediately so the rate of release
is determined by the rate of synthesis,
especially the synthesis of pregnenolone.

 Formed by altering the structures of amino
acids.
 Secreted by the
 -Thyroid gland
-Adrenal medulla
 -Hypothalamus
 -Pineal gland

 Synthesized from two(2) amino acids.
 Tyrosine – cateholamines(noradrenaline and
adrenaline).
 Tryptophan – precursor of melatonin

 Granules are released by exocytosis.
 Rate of release is regulated mainly by
secretion.

All hormones secreted from endocrine glands
are transported in the blood.
Steroid Hormones:
Steroid hormones and thyroid hormones are
lipid soluble and require a carrier protein to be
transported in the blood in order to reach their
target cell.

Non Steroid Hormones:
 Non steroid hormones tend to be water
soluble and as such they dissolve in the blood
plasma where they are transported to their
target cell.

Mechanism involved in
steroid and thyroid
hormone action:
 Endocrine gland secretes
a steroid hormone for
example
 Hormone enters target cell
by diffusing through the
cell membrane and enters
the nucleus.

 The hormone then bind
to the receptor molecule.
 The hormone-protein
complex then binds to
DNA and promotes the
synthesis of mRNA
 mRNA leaves the nucleus
and enters the cytoplasm
where it is translated to
proteins molecules.

Mechanism involved in non-
steroid hormones action
 Endocrine gland secretes a
non- steroid hormone like
insulin for example.
 The hormone is carried to
it’s target cell by the blood
plasma
 The hormone then binds to
its receptor site on the
membrane of it’s target cell

 The hormone receptor
binding activates
adenylate cyclase via a
G-protein.
 Adenylate cyclase then
causes ATP molecules to
be converted into cyclic
AMP (cAMP) molecules.

 cAMP then activates
various protein kinases
which phosphorylates
various protein
substrates.
 The activated protein
substrates induce
changes in metabolic
processes.
 Cellular changes are
recognized as the
hormone response.

 Baker, M, 2002. Albumin, steroid hormones
and the origin of vertebrates. Journal of
Endocrinology 175:121-127.
 Hole, John. Human Anatomy and Physiology.
Oxford, England. 1993

• Metabolism is the process of converting fuel from foods
into energy for the body to function.
• Hormone’s concentration in the plasma depends on;
1. Its rate of secretion by the endocrine gland.
2. Its rate of removal from the blood, either by;
 Excretion
 Metabolic Transformation
• The liver or kidneys are the major organs that excrete or
metabolize hormones. However they are not the only
routes for eliminating hormones. Sometimes the
hormones is metabolized by the cells upon which it acts.

In the case of
peptide
hormones,
endocytosis of
hormone-
receptor
complexes on
plasma
membranes
enables cells to
remove the
hormones rapidly
from their
surface and
catabolize them
intracellularly.
The receptors are
then often
recycled to the
plasma
membrane.
Metabolism of Peptide Hormones

 Catecholamine
and peptide
hormones are
excreted rapidly
or attacked by
enzymes in the
blood and
tissues thus
tend to remain
in the
bloodstream for
only brief
periods.
 In contrast,
because protein-
bound hormones
are less vulnerable
to excretion or
metabolism by
enzymes, removal
of the circulating
steroid and thyroid
hormones generally
takes longer.
Rate of Metabolism/Excretion of
the different types of Hormones

In some cases
metabolism of the
hormone after its
secretion activates
rather than inactivates
it. In other words, the
secreted hormone may
be relatively or
completely unable to
act upon a target cell
until metabolism
transforms it into a
substance that can act.
An Example is provided by
Testosterone:
Metabolism of Hormones

The thyroid gland directly affects metabolism as it is the
portion of the endocrine system responsible for secreting
hormones that control the rate at which the body’s cells burn
fuel for energy.
How does the Endocrine System control Metabolism?

Finally, there is another kind of
“activation” that applies to a few
hormones. Instead of the
hormone itself being activated
after secretion it acts
enzymatically on a completely
different plasma protein to split
off a peptide that functions as the
active hormone.

Summary of the processes
Metabolism and Excretion of
Hormones

Endocrine Cell
(alters the rate of
hormone secretion)
Ions or
Nutrients
Neurotransmitter
s
Hormones

Plasma concentration of specific
mineral ions or organic nutrients
directly control multiple hormone
secretions.
Major function is to regulate through
negative feedback:
oCa2+ homeostasis
oGlucose

 The Autonomic nervous system influences
endocrine glands.
oParasympathetic & Sympathetic inputs to
glands may occur, some of which are
inhibitory and others stimulatory.

 Tropic Hormone:
o Stimulates secretion of another hormone
o Stimulates the growth of the gland
 Some hormones in a multihormone
sequence inhibit the secretion of other
hormones.

Hormone Location of
Secretion
Effect
Anti-diuretic
Hormone
(ADH)
Pituitary gland
in the brain.
Water balance
in the kidney.
Thyroid
Stimulating
Hormone
(TSH)
Pituitary gland
in the brain.
Stimulates
thyroid gland
to produce
hormone
Thyroxine.

Disorder Definition
•Hyposecretion 1. Primary hyposecretion: too little
hormone secretion by endocrine
gland.
2. Secondary hyposecretion:
endocrine gland receiving too
little of its tropic hormones.
•Hypersecretion 1. Primary hypersecretion: too much
hormone being secreted by gland
on its own.
2. Secondary hypersecretion: gland
is excessively stimulated by its
tropic hormones.
•Hyporesponsiveness Target cells do not respond normally
to hormone.
Hyperresponsiveness Excessive gland response to
hormone.

 The pituitary gland lies in a pocket of the
sphenoid bone at the base of the brain , just
below the brain area which is known as the
hypothalamus.
 The pituitary is connected to the
hypothalamus by the infundibulum.
 The Pituitary gland has two adjacent lobes :
the anterior and posterior pituitary

 The axons of two clusters of hypothalamus
neurons passes down the infundibulum and ends
within the posterior pituitary
 There is no important neural connections
between the hypothalamus and anterior pituitary.
 The capillaries at the base of the hypothalamus
recombine to form the hypothalamo-pituitary
portal vessels

 The hypothalamo-pituitary portal vessels
passes down the stalk which connects the
hypothalamus and pituitary.
 This now enters the anterior pituitary where
they drain into a second capillary bed, the
anterior pituitary capillaries.
 This allows for a rapid response and limits
the amount of hormone that must be
synthesized to reach an effective blood
concentration.

 There are two posterior pituitary hormones :
1)Oxytocin
> Stimulates contraction of smooth muscle cells in
breasts
> Stimulates contraction of uterine smooth muscle
during labour
2)Vasopressin
> Acts on smooth muscle cells around blood vessels to cause
muscle contraction
> Acts within the kidneys to decrease water excretion in the urine
> Known as an antidiuretic hormone (ADH)

 The hormone moves down the axons to
accumulate at the axon terminals in the posterior
pituitary
 Neurotransmitters generate action potentials in
the neurons
 These now propagate to the axon terminals and
trigger the release of the stored hormone
 The hormones enter the posterior pituitary and
is carried away by blood to the heart

 Hypophysiotropic Hormones
- these are the hypothalamic hormones that regulate
anterior pituitary function
 Each of the hypophysiotropic hormones is the first in a
three-hormone sequence:
(1)A hypophysiotropic hormone controls the secretion
of
(2)an anterior pituitary hormone, which controls the
secretion of
(3) a hormone from some other endocrine gland
The last hormone then acts on its target cells

 Similar to that of the Anterior Pituitary hormones
with two differences :
1) The axons of the hypothalamic neurons that
secrete the hypophysiotropic hormones remain
in the hypothalamus, ending in its median
eminence.
2) the hypophysiotropic hormones enter capillaries
in the median eminence of the hypothalamus
that do not directly join the main bloodstream,
but empty into the hypothalamo-pituitaryportal
vessels, which carry them to the anterior
pituitary

Hormone Function
CRH Stimulates the release of
ACTH
TRH Stimulates the release of
TSH
GRH Stimulates the release of GH
GHIH Inhibits the release of GH
GnRH Stimulates the release of FSH
& LH
PIH (Dopamine) Inhibits the release of
Prolactin

SYNTHESIS, ACTIONS OF THYROID
HORMONES & CONTROL OF THYROID
FUNCTION

 What are thyroid hormones?
Basically hormones that are produced by the
thyroid gland, which have diverse effects
throughout the human body.
 The thyroid gland produces two iodine-
containing molecules of physiological
importance:
1) thyroxine (T4)
2) triiodothyronine (T3)

 Thyroxine (T4) is generally converted to
triiodothyronine(T3) by enzymes known as
deionases in target cells.
 T4 is the major secretory product of the
thyroid and the total T4 concentrations are
higher in the blood. However T3 is the major
thyroid hormone.

 The thyroid gland is a bi-lobed structure that
sits within the neck, straddling the trachea.

 The thyroid gland is composed of numerous
follicles each made up of an enclosed sphere
of highly specialized cells surrounding a core
containing a protein rich material called
colloid.

Step 1:
 Synthesis begins when circulating iodide is
cotransported with sodium ions across the
follicular cell plasma membrane.
N.B. Iodine cannot diffuse back into the
interstitial fluid once it is in the cell. This is
called iodide trapping.

Step 2:
 The trapped, negatively charged iodide ions
diffuse down their electrical and concentrated
gradients to the lumenal border of the follicular
cells
Step 3:
 The colloid of the follicles contains large
amounts of protein called thyroglobulin(TG). The
iodine that diffuses to the colloid is rapidly
oxidized at the hormonal surface of the follicular
cells to the iodine free radicals. The free radicals
are then attached to the phenolic rings of the
tyrosine molecules within the amino acid
structure of TG.

 Thyroid peroxidase- The enzyme responsible
for oxidizing iodides and attaching them to
tyrosines and thyroglobulin in the colloid.
N.B. Thyroglobulin and thyroid peroxidase are
synthesized by follicular cells. Iodines can be
added either of two positions on a given
tyrosine within a thyroglobulin.
 Monoiodotyrosine (MIT) – a tyrosine with one
iodide attached .
 Diiodotyrosine (DIT) – a tyrosine with two
iodines attached.

Step 4:
The phenolic ring of either a molecule of DIT
or MIT are removed from the remainder of its
tyrosine and is coupled with another DIT on
the thyroglobulin molecule(reaction mediated
by thyroid peroxidase)
N.B. If two DIT molecules are coupled the result
in tyrosine (T4 ). If one DIT and one MIT are
coupled the result is T3.

Step 5:
When thyroid hormone is needed in the
blood, extensions of the colloid-facing
membranes of the follicular cells engulf
proportions of the colloid(with the iodonated
thyroglobulin) by endocytosis.
Step 6:
The thyroglobulin with its coupled MITs and
DITs is brought into contact with lysosomes
in the cell interior.

Step 7:
Proteolysis of thyroglobulin releases T3 and
T4, which then diffuses out of the follicular
cell into the interstitial fluid and from ther
back into the blood.

Essentially all of the actions of the follicular cells
are stimulated by thyroid stimulating hormone,
(TSH) which is stimulated but thyrotropin- releasing
hormone, (TRH)
The basic control mechanism of TSH production is
the negative feedback action of TH on the anterior
pituary, and to the lesser extent the hypothalamus.

 TSH not only stimulates T3 and T4 production
but it also:
 Increases protein synthesis in follicular cells.
 Increases DNA replication and cell division
 Increases the amount of rough endoplasmic
reticulum and other cellular machinery required
by follicular cells for protein synthesis.
N.B. When TSH levels exceed normalcy in the
thyroid cell it undergoes hypertrophy. This
causes the cell to increase in size. Enlarged
thyroid glands from any cause is called a goiter.

 Thyroid hormone receptors are present in the
nuclei of most cells of the body, unlike
receptors for many other hormones, whose
distribution is more limited. Thus the actions
of T3 and T4 are wide spread and may affect
many organs and tissues.

They are three main actions of thyroid
hormones:
1) Metabolic Action
2) Permissive Action
3) Growth and Development

 Thyroid hormones(TH) have several effects on
carbohydrates and lipid metabolism, although
not to the extent of other hormones e.g
insulin. However, TH stimulates carbohydrate
absorption from the small intestine and
increases fatty acid release from adipocytes.
 These actions provide energy to maintain
metabolic rate at a high level, and are
consistent with one of the major actions of
TH, which is to stimulate the activity of
Na+/K+ -ATPases throughout the body.

 ATP is consumed by Na+/K+ -ATPases at a
high rate due to TH activation, the cellular
stores of ATP must be maintained by
increased metabolism of fuels.
 The calorigenic action of TH represents a
significant fraction of the total heat produced
each day in a typical human.

 Many of the actions of TH are attributable to
its permissive effects on catecholamines.
 TH up-regulates beta-adrenergic receptors in
many tissues:
 Heart
 Nervous system
Increased levels of TH potentiates the
actions of the catecholamines even though
the catecholamines are within normal levels.

 TH is needed for normal production of
growth hormone.
Therefore, in the absence of TH, growth in
children is decreased.
 TH is one of the most important
developmental hormones for the nervous
system.
Absence of TH during fetal life results in
poorly developed nervous system and a form
of mental retardation called cretinism.

1) PHYSIOLOGICAL
FUNCTIONS OF
CORTISOL
2) FUNCTIONS OF
CORTISOL IN STRESS

 Cortisol is a steroid hormone.
 It is produced when there isn't
enough cortisol in the blood
(to maintain homeostasis in
the body) or to deal with
stress.

 It is produced by the adrenal
glands. When the body needs
cortisol, a message is sent to the
hypothalamus via the sympathetic
nervous system to produce the
hormone CRF. The CRF activates
the pitutary gland which then
produces the hormone
ACTH. This in turn alerts the
adrenal gland which stimulates
the adrenal cortex to produce
cortisol.

 Basal cortisol levels help maintain
normal blood pressure. Cortisol exerts
influence on the reactivity to
epinephrine and norepinephrine of
muscle cells that surround blood
vessels.
 Basal levels of cortisol are also
essential in maintaining cellular
concentrations of certain enzymes
involved in metabolic homeostasis.

 Cortisol also serves as an anti-
inflammatory agent and also has anti-
immune functions –
Anti-inflammatory:
1) Cortisol inhibits the production of both
leukotrienes and prostaglandins.
Leukotrienes and prostaglandins are
both involved in inflammation.
2) Cortisol also stabilizes lysosomal
membranes in damaged cells (preventing
the release of their proteolytic contents).

3) Cortisol reduces capillary
permeability in injured areas (thus
reducing fluid leakage to the
interstitium).
Anti-Immune:
 Cortisol suppresses the growth and
function of key immune cells. The
importance of this is that if cortisol
was absent, the body would over react
to minor infections and auto-immune
diseases can result. It, in essence, acts
as a "brake" on the immune system.

 Cortisol is also important during fetal
and neonatal life. It serves to allow for
proper differentiation of numerous
tissues and glands including various
parts of the brain, the adrenal
medulla, the intestine and most
notably the lungs (cortisol produces
surfactant which reduces surface
tension in the lungs).

1) Effects on Organic Metabolism :
- Stimulation of protein catabolism in
bone, lymph, muscle and elsewhere.
- Stimulation of liver uptake of amino
acids and their conversion to glucose
(gluconeogenesis).
- Maintenance of plasma glucose levels.
- Stimulation of triglyceride catabolism
in adipose tissue, with release of
glycerol and fatty acids in the blood.

2) Inhibition of inflammation and
specific immune responses.

3) Inhibition of nonessential functions
(so that all resources can be put
towards dealing with the stressful
situation).

4) Enhanced vascular reactivity
(increased ability to maintain
vasoconstriction in response to
norepinephrine and other stimuli so
that the body can engage in fight or
flight).

 Adrenal insufficiency-
Addison’s Disease
 Cushing’s syndrome
 Diabetes Mellitus
 Growth disorders
 Thyroid Disorders

 What is adrenal insufficiency?
 Adrenal insufficiency is an endocrine or
hormonal disorder that occurs when the
adrenal glands do not produce enough of
certain hormones.
 It refers to any situation in which the levels of
cortisol are chronically lowers than normal.

 Primary Adrenal Insufficiency
 Secondary Adrenal Insufficiency

 Also referred to as ADDISON’S
DISEASE
 Occurs when the adrenal glands are
damaged and cannot produce enough
of the hormone cortisol and often the
hormone aldosterone.

 The most common cause is due to the autoimmune
attack in which immune system mistakenly
recognizes some component of a person’s own
adrenal cells as “foreign”.
 It is due to loss of adrenal cortical function which
may occur for example, when an infectious disease
such as tuberculosis, HIV, or fungal infections,
infiltrate the adrenal gland and destroy them.
 Tumours

 Imbalance of sodium, potassium and water in the
blood
 Hypotension (low blood pressure)
 Chronic diarrhoea
 Darkening of the skin-patchy skin colour
 Paleness
 Extreme weakness
 Fatigue
 Loss of appetite
 Mouth lesions on the inside of a cheek (buccal
mucosa)

 Nausea and vomiting
 Slow, sluggish movement
 Unintentional weight loss
 Salt craving

 The diagnosis is made by measuring plasma
concentrations of cortisol. Tests may also
show increased potassium level, low blood
pressure, low serum sodium. However, sex
hormones will be at normal levels.
 Addison’s disease may be misdiagnosed as
chronic fatigue syndrome or even as a
psychological disorder because some patients
may exhibit anxiety or emotional problems.

 This disease requires daily oral administration
of glucocorticoids and mineralocorticoids.
 Also, the patient must carefully monitor his
or her diet to ensure adequate consumption
of carbohydrates and controlled potassium
and sodium intake.

 Secondary Adrenal Insufficiency can be traced
to a lack of ADENOCOTICOTROPIC HORMON
(ACTH)
 Aldosterone production is usually not
affected.

 ACTH is a polypeptide tropic hormone
produced and secreted by the anterior
pituitary gland and is produced in response
to biological stress.
 It’s principle effects are increased production
and release of corticosteroids and, as the
name suggests, cortisol from the adrenal
cortex.

 A temporary form of this disease may occur
in person who has been taking a synthetic
glucocorticoid hormone for a long time and
then stops, either abruptly or gradually.
(Glucocorticoid block the release of both
ACTH and CRH).
 Another cause is the surgical removal of the
noncancerous ACTH producing tumours of
the pituitary glands that cause Cushing’s
disease.

 Adrenal Insufficiency is a disorder that occurs
when the adrenal glands do not produce enough
of the hormone cortisol.
 Primary Adrenal Insufficiency, also called
Addison’s disease, occurs when the adrenal
glands are damaged and cannot produce enough
of the hormone cortisol and often the hormone
aldosterone.
 Secondary Adrenal Insufficiency occurs when the
pituitary gland fails to produce enough ACTH, a
hormone that stimulates the adrenals to produce
cortisol. If ACTH output is too low, cortisol
production drops.

 Cushing’s Syndrome is a hormonal disorder
caused by prolonged exposure of the body’s
tissues to high levels of the hormone cortisol
in the blood, even in a non-stressed
individual.

 Due to primary effect e.g. A cortisol secreting
tumour on the adrenal gland.
 Due to secondary effect, usually due to ACTH
secreting tumour of the pituitary gland.
 It may caused because people take
glucocorticoid hormones.
 May be caused due to overproduction of
cortisol in the body.

 The increased catabolism may produce such a large
quantity of precursors for hepatic gluconeogenesis
that the blood sugar levels increase as observed in
diabetes.
 The increased blood levels of cortisol tend to
promote uncontrolled catabolism of bone, muscle,
skin and other organs. The bone strength diminishes
and can lead to osteoporosis, muscle weakens and
skin become thinned and easily bruised.
 There is a possibility of immunosuppression which is
brought about by the anti-immune actions of
cortisol.

 It is associated with the loss of fat mass from
the extremities and with the redistribution of
fat in the trunk, face and back of the neck.
Obesity can occur.
 A possibility of developing hypertension due
to the pharmacological effects of cortisol,
including cortisol’s ability to potentiate the
effects of epinephrine and norepinehrine on
the heart and blood vessels.

 Most people have severe fatigue, weak
muscles, high blood pressure and high blood
sugar.
 Women usually have excess hair growth on
their faces, necks, chests, abdomens, and
thighs. Their menstrual periods may become
irregular or stop.
 Men have decreased fertility with diminished
or absent desire for sex.

 Treatment depends on the specific reason for
cortisol excess and may include surgery,
radiation, chemotherapy or the use of cortisol
inhibiting drugs.

 Often referred to as Diabetes, is a group of
metabolic diseases in which a person has
high blood sugar levels, either because the
body does not produce enough insulin, or
because cells do not respond to the insulin
that is produced.
 There are 3 main types:
 TYPE I DIABETES
 TYPE II DIABETES
 GESTATIONAL DIABETES

 Insulin is the principle hormone that regulates uptake of
glucose from the blood into most cells (primarily muscle
and fat cells, but not central nervous system cells)
 Insulin is produced by special cells, called beta cells, in the
pancreas. (pancreas is found behind your stomach)
 Therefore, deficiency of insulin or the insensitivity of its
receptors plays a central role in all forms of diabetes
mellitus.
 Insulin is also the principle control signal for conversion of
glucose to glycogen storage in the liver and muscle cells.

 Type I diabetes melitus is characterized by the
loss of insulin-producing beta cells of the Islets
of Lagerhans in the pancreas leading to insulin
deficiency.
 This type of diabetes ca be further classifies as
immune-mediated or idiopathic, where beta cell
loss is a T-cell mediated autoimmune attack.
 Beta cells produce little or no insulin and as a
result glucose builds up in the bloodstream
instead of going into the cells.

 Type II diabetes mellitus is characterized by insulin
resistance which may be combined with relatively reduced
insulin secretion.
 The insulin receptors are believed to be the defective
responsiveness of body tissues to insulin.
 Due to the insulin resistance which means that the fat,
liver and muscle cells do not respond correctly to insulin,
the blood sugar does not get into these cells to be stored
for energy.
 When the sugar cannot enter cells, there are high levels of
sugar build up in the blood. This refers to
HYPERGLYCEMIA.

 In the early stage of type II diabetes, the most
predominantly abnormality is reduced insulin
sensitivity. Hence, at this stage hyperglycaemia
can be reversed by a variety of measures and
medications that can improve insulin sensitivity
or reduce glucose production by the liver.
 Type II diabetes usually occurs slowly over time
and most people with this disease are
overweight. (increased fat makes it harder for
your body to use insulin the correct way)

 This type of diabetes only occurs in some women
during pregnancy.
 For moms-to-be the body need additional insulin,
therefore the pancreas dutifully secretes more of it.
However, if the pancreas can’t keep up with the
increased insulin level, the blood glucose levels rise
too high.
 Between 2 and 10 percent of expectant mothers
develop this condition, making it one of the most
common health problems in pregnancy. Most women
don’t remain with gestational diabetes after
pregnancy.

 Once someone has had gestational diabetes,
she is at a higher risk for getting aging
during future pregnancy and for developing
diabetes later in life.
 If untreated, gestational diabetes can damage
the health of the foetus and such risks
include macrosomia (high birth weight),
congenital cardiac and central nervous
system anomalies, and skeletal muscle
malformations.

 Symptoms may develop rapidly (weeks or months) in type I
diabetes, while in type II diabetes they usually develop
much more slowly and may be subtle or absent.
 Classic symptoms are polyuria (frequent urination),
polydipsia (increased thirst) and polphagia (increased
hunger).
 Changes in the shape of the lenses in the eyes, resulting in
vision changes.
 People may also present with diabetic ketoacidosis, a state
of metabolic dysregulation characterized by the smell of
acetone.

 A rapid, deep breathing known as Kussmaul
breathing.
 Nausea
 Vomiting
 Abdominal pain
 Altered states of consciousness

Comparison of type 1 and 2 diabetes
Feature Type 1 diabetes Type 2 diabetes
Onset Sudden Gradual
Age at onset
Any age
(mostly young)
Mostly in adults
Body habitus Thin or normal Often obese
Ketoacidosis Common Rare
Autoantibodies Usually present Absent
Endogenous insulin Low or absent
Normal, decreased
or increased
Concordance
in identical twins
50% 90%
Prevalence Less prevalent
More prevalent
- 90 to 95% of
U.S. diabetics

 When you're stressed, your blood sugar levels
rise. Stress hormones like
epinephrine and cortisol kick in since one of
their major functions is to raise blood sugar
to help boost energy when it's needed most.
Think of the fight-or-flight response. You
can't fight danger when your blood sugar is
low, so it rises to help meet the challenge.
Both physical and emotional stress can
prompt an increase in these hormones,
resulting in an increase in blood sugars.

 People who aren't diabetic have compensatory
mechanisms to keep blood sugar from swinging
out of control. But in people with diabetes, those
mechanisms are either lacking or blunted, so
they can't keep a lid on blood sugar. When blood
sugar levels aren't controlled well through diet
and/or medication, you're at higher risk for many
health complications, including blindness, kidney
problems, and nerve damage leading to foot
numbness, which can lead to serious injury and
hard-to-heal infections. Prolonged elevated
blood sugar is also a predecessor
to cardiovascular disease, which increase the risk
of heart attacks and strokes

 Anything upsetting like going through a
breakup or being laid off is certainly
emotionally draining. Being down with
the flu or suffering from a urinary tract
infection places physical stress on the body.
It's generally these longer-term stressors that
tax your system and have much more effect
on blood sugar levels.

 Bone is a special connective tissue made up of
several cell types surrounded by a collagen matrix,
called osteoid, upon which are deposited minerals,
particularly the crystals of calcium and phosphate
known as hydroxyapatite.
 A growing long bone is divided into the ends, or
epiphyses, and the remainder, the shaft.
 The portion of each epiphysis that is in contact with
the shaft is a plate of actively proliferating cartilage,
known as the epiphyseal growth plate.

epiphyses
shaft
epiphyses
Epiphyseal
growth
plate
Marrow
cavity
Diagram Showing Simple Structure of the Bone.

 There are three types of bone cells:-
1) osteoblasts
2) osteocytes
3) osteoclasts

oesteobla
sts
osteoclasts
osteocyte
Calcified
matrix

 Osteoblasts are the bone-forming cells.
 They secrete collagen to form a surrounding matrix,
which then becomes calcified.
 Once surrounded by calcified matrix, the osteoblasts
are called osteocytes.
 The osteocytes have long cytoplasmic processes that
extend throughout the bone and form tight junctions
with other osteocytes.
 Osteoclasts are large multinucleated cells that break
down (resorb) previously formed bone by secreting
hydrogen ions, which dissolve the crystals, and
hydrolytic enzymes, which digest the osteoid.

 At the shaft edge of the epiphyseal growth plate, the
osteoblasts convert the cartilaginous tissue at this
edge to bone, while new cartilage is simultaneously
being laid down in the interior of the plate by cells
called chondrocytes.
 The epiphyseal growth plate remains intact, actually it
usually widens and is gradually pushed away from the
centre of the bony shaft as the latter lengthens.

Epiphyseal
growth plate
Area where new
cartiliage is
being laid down
by
Chrondrocytes
Shaft edge
where
osteoblasts
convert
cartilaginous
tissue to bone.
epiphyse
s
shaft

 As long as the epiphyseal growth plate exists, linear
growth of the shaft can take place. However, it ceases
when the plates are themselves converted to bone as
a result of hormonal infuences at puberty.
 This is known as epiphyseal closure and occurs at
different times in different bones.
 Therefore, a person’s bone age can be determined by
x-raying the bones and determining which ones have
undergone epiphyseal closure.

 An important factor here is that bone is constantly
being “remodeled” by the osteoblasts and
osteoclasts working together.
 The purpose of remodeling is to regulate calcium
homeostasis, repair micro-damaged bones (from
everyday stress) but also to shape and sculpture the
skeleton during growth.
 Osteoclasts resorb old bone, and then osteoblasts
move into the area and lay down new matrix, which
becomes calcified.

 This process is dependent, in part, on the stresses
imposed on the bones by gravity and muscle tension,
both of which stimulate osteoblastic activity.
 When osteoblasts are stimulated there is an increase
in the bone mass through increased secretion of
osteoid and by inhibiting the ability of osteoclasts to
break down osseous tissue.
 Bone building through increased secretion of osteoid
is stimulated by the secretion of growth hormone by
the pituitary, thyroid hormone and the sex hormones
(estrogen and androgens)
 It is also influenced by many other hormones, as
summarized in the table below.

Hormones that favor bone formation and increased
bone mass
 Insulin
 Growth hormone
 Insulin-like growth factor I (IGF-I)
 Estrogen
 Testosterone
 1,25-dihydroxyvitamin D3 (influences only
mineralization, not matrix)
 Calcitonin
Hormones that favor increased bone resorption and
decreased bone mass
 Parathyroid hormone
 Cortisol
 Thyroid hormones (T4 and T3)

GROWTH HORMONE (GH)
 GH causes growth of the epiphyseal regions of the
long bones.
 Growth of the long bone can be monitored by
measuring the incorporation of sulphur (35S) into the
epiphyseal cartilage.
 It is said that GH acts indirectly on bones by way of
the production of a sulfation factor.
 This sulfation factor is known to consist of several
peptides referred to as somatomedins.
 Injected radiolabeled GH rapidly localized to the liver
rather than to the epiphyses of the long bones.

 Somatomedin is generally used to refer to those
growth factors found in the plasma that are under
the control of GH, have insulin –like properties, and
promote the incorporation of sulfate into cartilage (
the somatomedin hypothesis).
 Insulin-like growth factors I and II (IGF-I and IGF-II)
are two substances isolated from the plasma in pure
or rather pure form fulfill these criteria.
 The peptides bear some sort of structural
relationship to proinsulin and therefore, exhibit
some affinity for insulin receptors.

 GH does not have a direct effect on cartilage but
rather stimulates chondrogenesis and subsequent
growth indirectly by way of somatomedins,
according to the somatomedin hypothesis.
 The number of IGF-I immunoreactive cells in the
proliferative zone is increased.
 IGF-I is produced in the proliferative chondrocytes in
the growth plate in response to GH.
 GH can induce local IGF-I production in the
epiphyseal plate at the level of both mRNA and
protein.

 GH, but not IGF-I, stimulates the multiplication of the
slowly cycling (label-retaining) cells in the germinal
layer of the epiphyseal plate.
 Fact is locally infused IGF-I is able to increase
epiphyseal width as well as longitudinal bone growth.

 Children manifest two periods of rapid increase in
height;
1) during the first two years of life, and
2) during puberty
 Note that increase in height is not necessarily
correlated with the rates of growth of specific
organs.
 The pubertal growth spurt lasts several years in
both sexes, but growth during this period is
greater in boys.
 This, plus the fact that boys grow more before
puberty because they begin puberty approximately
two years later than girls, accounts for the
differences in average height between men and

 Graph below shows the relative growth in the brain,
total body height and reproductive organs.

 The primary factors influencing growth are:
1)The adequacy of nutrient supply
2) Freedom of diseases
 Lack of sufficient amounts of any of the essential
amino acids, essential fatty acids, vitamins, or
minerals interferes with growth.
 Total protein and sufficient nutrients needed to
provide energy must also be adequate.
 The growth-inhibiting effects of malnutrition can be
seen at any time of development but are most
profound when they occur very early in life.
 Thus, maternal malnutrition may cause growth
retardation in the fetus.

 Since low birth weight is strongly associated with
increased infant mortality, prenatal malnutrition
causes increased numbers of prenatal and early
postnatal deaths.
 Moreover, irreversible stunting of brain development
may be caused by prenatal malnutrition. During
infancy and childhood, too, malnutrition can
interfere with both intellectual development and
total body growth.
 Following a temporary period of stunted growth due to malnutrition or illness,
and given proper nutrition and recovery from illness, a child manifests a
remarkable growth spurt (catch-up growth) that brings the child up to the
normal height expected for his or her age. The mechanism that accounts for
this accelerated growth is however, unknown.

 Human growth requires hormones.
 A hormone is a chemical released by a cell
or a gland in one part of the body that
sends out messages that affects particular
cells in other parts of the organism.
 Only a small amount of hormone is
required to alter cell metabolism.

The most important hormones to human
growth are:-
 Growth hormone
 Insulin-like growth factors I and II
 Thyroid hormones
 Testosterone
 Estrogens

 There is also a large group of peptide growth factors
which includes the insulin-like growth factors and
most of these growth factors act as paracrine and
autocrine agents.
 Paracrine- chemical signals that diffuse into the area
and interact with receptors on nearby cells. The
release of neurotransmitter at synapses in the nervous
system.
 Autocrine - the cell signals itself through a chemical
that it synthesizes and then responds to. Autocrine
signaling can occur solely within the cytoplasm of the
cell or by a secreted chemical interacting with
receptors on the surface of the same cell agents.

 This type of hormone stimulate differentiation and or
sometimes cell division of specific cells.
 Generally the term used for a chemical which that
stimulates cell division is called a mitogen.
 Growth is also modulated by peptide growth
inhibiting factors which inhibit cell division in
specific tissues of the body.

 Growth hormone exerts its cell division stimulating effect
not directly on cells but rather indirectly through the
mediation of a mitogen whose synthesis and release are
induced by growth hormone.
 This mitogen is called insulin-like growth factor I
(IGF-I)
 Under the influence of growth hormone, IGF-I is secreted
by the liver, enters the blood and functions as a hormone.

 The importance of IGF-I in mediating the major
growth-promoting effect of growth hormone is shown
by the fact that dwarfism cannot be due only to
decreased secretion of growth hormone but also to
decreased production of IGF-I or even failure of the
tissues to respond to IGF-I.
 IGF-I is required for normal fetal total-body growth
and, specifically, for normal maturation of the fetal
nervous system.
 The stimulus for IGF-I secretion during prenatal life
is however unknown at this time.

 Finally, it should be noted that there is another
messenger—insulin-like growth factor II (IGF-
II)—that is closely related to IGF-I.
 IGF-II, the secretion of which is independent of
growth hormone, is also a crucial mitogen during
the prenatal period.
 It continues to be secreted throughout life, but its
postnatal function is unknown.

 The growth hormone is secreted by the anterior
pituitary gland.
 It has little or no effect on fetal growth however it is
the most important hormone for post natal growth.
 Main growth promoting effect is the stimulation of
cell division in many particular tissue regions.

 Growth hormone promotes bone lengthening by
stimulating maturation and cell division of the
chondrocytes in the epiphyseal plates and thereby
continuously widens the plates and providing more
cartilage for formation of bone.
 *Chondrocytes are cells found in the cartilage.
 They produce and maintain the cartilaginous matrix
which consists mainly of collagen and proteoglycan.

 The Thyroid hormones (TH) includes:-
 Thyroxine ( T4) which is secreted by the follicular
cells of the thyroid gland.
 Tri-iodothyronine (T3) is released from the pituitary
gland. It affects almost every physiological process
in the body, including growth and
development, metabolism, body temperature and
heart rate.

 Both are essential for normal growth because they are
required for both the synthesis of growth hormone
and the growth promoting effects of that hormone.
 Infants and children who are deficient in Thyroid
production usually show signs of retarded growth due
to the slow formation of bone growth.
 This deficiency is termed hypothyroidism.

 Thyroid hormones are also essential for normal
development of the central nervous system during
fetal life.
 Inadequate production of maternal and fetal thyroid
hormones due to severe iodine deficiency during
pregnancy is one of the most occur able instances yet
still the most common preventable causes of mental
retardation.
 This is termed Endemic Cretinism.

 This effect on the brain’s development must be
distinguished from other effects TH exerts on the
nervous system throughout the human life and not
just during infancy.
 Therefore a hypothyroid (under secretion of TH)
person will exhibit sluggish reactions and poor
mental functions, however these effects are
completely reversible at times with administration of
Thyroid hormones.
 So too a person with hyperthyroidism (excess
secretion of TH) shows signs of being jittery and
hyperactive.

 Insulin is a hormone central to regulating
carbohydrates and fat metabolism in the body.
 It causes cells in the liver, muscle and fat tissues to
take up glucose from the blood and store it as
glycogen in the liver and muscles.
 Therefore it is obvious that an adequate amount of
insulin is necessary for normal growth since Insulin
can be referred to as an anabolic hormone.

 Human insulin is a peptide hormone and is produced
in the Islets of Langerhans in the pancreas.
 Its inhibiting effect on protein degradation is
particularly important when it comes to growth.
 Insulin exerts direct and specific growth promoting
effects on cell differentiation and cell division during
fetal life.
 Insulin is also required for the normal production of
Insulin Growth Factor I.

 Sex hormones include both Testosterone and
Estrogen.
 Secretion of these hormones begins at around ages 8-
10 and gradually increases to reach a certain
concentration over the years.
 Growth of the long bones and vertebrae requires an
increased production of sex hormones.

 The major growth promoting effect of the sex
hormones is to stimulate the secretion of growth
hormone and insulin growth factor I.
 The sex hormones does not only stimulate bone
growth but also stops it by inducing epiphyseal
closure.
 This double effect of the sex hormones reiterates the
pattern of growth development in teenagers.

 Testosterone is an anabolic steroid hormone.
 It is the main, male sex hormone .
 Testosterone is primarily secreted in the testes of males and
the ovaries of females.
 However small amounts are also secreted by the adrenal gland.
 In men, testosterone plays a key role in the development of
male reproductive tissues such as the testis and prostate as
well as promoting secondary sexual characteristics such as
increased muscle, bone mass and the growth of bodily hair

 In addition, testosterone is essential for health and
well-being as well as the prevention of Osteoporosis.
 Testosterone exerts a direct anabolic effect on protein
synthesis in many non reproductive organs and
tissues of the body.
 This is what accounts for the increased muscle mass
of men, as compared with that of women.

 Estrogen is a hormone that comprises a group of compounds,
including estrone, estroidol and estroil.
 It is the main sex hormone in women and is essential to the
menstrual cycle.
 Estrogen is manufactured mostly in the ovaries, by developing
egg follicles. In addition, estrogen is produced by the corpus
luteum in the ovary, as well as by the placenta.
 Although estrogen exists in men as well as women, it is found
in higher amounts in women, especially those capable of
reproducing.
 Estrogen contributes to the development of secondary sex
characteristics, which are the defining differences between
men and women that don’t relate to the reproductive system.

 In women, these characteristics include breasts, a widened
pelvis, and increased amounts of body fat in the buttock, thigh
and hip region.
 Estrogen also contributes to the fact that women have
less facial hair and smoother skin then men.
 Estrogen is an essential part of a woman’s reproductive
process. It regulates the menstrual cycle and prepares the
uterus for pregnancy by enriching and thickening the
endometrium.
 Two hormones, the luteinizing hormone (LH) and the follicle
stimulating hormone (FSH), help to control how the body
produces estrogen in women who ovulate.

Effector sites for Ca 2+ Homeostasis
19
7

Why hormones are important in calcium
homeostasis?
 Extracellular Ca 2+ concentration normally
remains within a narrow range i.e. approx. 1
mM, or 10,000 times the basal concentration
of free calcium within cells.
 Large deviations in any direction from this
range would be catastrophic.
19
8

 For e.x. a low plasma calcium
concentration increases the excitability
of nerve and muscle plasma membranes.
 Conversely, a high plasma
concentration causes cardiac
arrhythmias (a.k.a irregular heart beat)
as well as depressed neuromuscular
excitability via its effects on membrane
potential.
19
9

 Calcium homeostasis depends on the
interplay among bone, the kidneys and
gastrointestinal tract.
20
2

 The activities of the gastrointestinal tract and
kidneys determine the net intake and output
of Ca 2+ for the entire body.
 However, interchanges of Ca 2+ between
extracellular fluid and bone do not alter
total-body balance, but change the
distribution of Ca 2+ within the body.
20
3

Bone
 Approx 99% of total-body Ca 2+ is contained
in the bone. Therefore, flux of Ca 2+ into and
out of the bone in controlling plasma Ca 2+
concentration is very important!
 Bone is a special connective tissue consist of:
 Collagen matrix called the osteoid
 a.k.a hydroxapatite because of Ca2+ and P04 deposits
20
4

 In some cases, bones have central marrow
cavities where blood cells form
 Approx. 1/3 of a bone by weight is osteoid
and 2/3 is mineral
 Three types of bone cells involved in bone
formation:
1. Osteobasts
2. Osteocytes
3. Osteoclasts
20
5

 Osteoblasts are the bone-forming cells. They
secrete collagen to form a surrounding
matrix which becomes calcified
(mineralization)
 Once surrounded by the calcified matrix, the
osteoblasts are called osteocytes
 Osteoclasts are large, multinucleated cells
20
7

 W.r.t to Ca 2+ homeostasis, many hormones
and a variety of autocrine/paracrine growth
factors produced locally in the bone, play an
important role
 Only the parathyroid hormone is primarily
controlled by plasma calcium concentration
20
8

Kidneys
 They eliminate soluble waste via blood
filtration
How?
 This process involves cells in the tubules that
are the functional units of kidneys. They
recapture most of the necessary solutes that
got filtered to minimize loss of vital minerals
in urine (i.e. calcium)
20
9

 Therefore, urinary excretion of Ca 2+ is the
difference between the amount filtered and
amount re-absorbed
 The control of Ca 2+ excretion is mainly via
re-absorption.
 Re-absorption decreases when plasma [Ca 2+
] increases and when plasma [Ca ]2+
decreases re-absorption increases
21
0

Gastrointestinal Tract
 Normally absorbs solutes such as Na+, K+ ,
but a considerable amount of ingested Ca2+
leaves the body via the G.I tract along with
feces.
 Hormonal control of this absorptive process
is the main means for regulating total-body
calcium balance, which will be discussed next
21
1

Take home message
Hormones regulate the levels of calcium in the
body via effector sites ( These are?)
Bone :- By constant remodeling via interaction
between osteoblasts and osteoclass which
determines bones mass and provides a means
of raising or lowering Ca2+ concentration
which is under hormonal control.
Kidney:- By regulating the amount of Ca2+
excreted in urine is the difference between
amount filtered and amount re-absorbed, in
which the latter is under hormonal control.
Andrew Grant
21
2

 Metabolic bone disease refers to
abnormalities of bones caused by a broad
spectrum of disorders.
 These disorders are to be differentiated from
a larger group of genetic bone disorders
whereas in this case there is a defect in a
specific signaling system(the endocrine
system)or cell type that causes the bone
disorder.

 PTH is the most important hormone in
calcium homeostasis.
 Released in response to low blood calcium
levels.
 Disorders of this system are grouped
according to their effect on PTH
 There are two(2) groups.
 -Hyperparathyroidism(excess of PTH)
 -Hypoparathyroidism(deficiency of PTH)

 Hypercalcemia refers to a condition in which
there is to much calcium in the blood.

 It is the excessive release of PTH.
 All actions of PTH raise calcium levels
 Main causes are
 -Parathyroid gland adenoma
 -Diffuse Parathyroid gland hyperplasia
 Symptoms include unexpected bone
weakness etc.
 There are three (3) treatmeant options.

 Many conditions can cause hypocalcaemia.
 Osteomalacia is a feature of secondary
hyperparathyroidism.
 Hypocalcaemia and excess PTH cause the
following symptoms eg. mood changes, etc.
 Causes of secondary hyperparathyroidism
 -chronic renal failure
 -vitamin D deficiency

 Deficiency of PTH.
 Causes the usual symptoms of hypocalcaemia
without the osteomalacia.
 Main causes are
 -Complications of thyroid or parathyroid
surgery.
 -Idiopathic hypoparathyroidism – an
autoimmune disorder.
 -Pseudohypoparathyroidism

 Caused by reduced osteoblast activity.
 New bone is not formed and microfractures
cannot be repaired so the bones become thin
and brittle.
 Caused by a deficiency of oestrogen or
testosterone.
 Main treatments are dietary calcium, vitamin
D supplements and hormone replacement
therapy.


Endocrinology

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